# Patent

## Title
Therapeutic peptides

## Abstract

Therapeutic peptides having guanylyl cyclase C agonist activity are disclosed. The therapeutic peptides are analogues of the E. coli STa peptide with non-natural amino acid, isosteric or D-amino acid substituents. The therapeutic peptides are useful in the treatment of chronic ideopathic constipation, inflammatory bowel disease, and other diseases. Pharmaceutical compositions comprising the therapeutic peptides are also disclosed.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This Application is the National Phase under 35 U.S.C. §371 of PCT International Application No. PCT/US2011/039572 which has an international filing date of Jun. 8, 2011, which claims priority to 61/352,973 filed on Jun. 9, 2010. The entire contents of these applications listed above are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
The present invention relates to methods and compositions for the treatment of gastrointestinal disorders, cancer, cardiovascular disorders, obesity, benign prostatic hyperplacia, disorders of the lung, disorders of the eye, inflammatory disorders, and other disorders. In particular the invention is useful for the treatment of disorders of the gastrointestinal tract, including constipation, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, diarrhea, ulcerative colitis and other gastrointestinal digestive or motility disorders. The compounds disclosed herein are peptides and peptide analogues which bind to the cellular receptor protein guanylyl cyclase (GC) or Guanylate Cyclase C (also named GCC, GC-C, Guanylyl cyclase C, GUC2C, GUCY2C, guanylate cyclase 2C, heat-stable enterotoxin receptor, hSTAR, intestinal guanylate cyclase, STAR, STA receptor, guanylate cyclase C receptor, GCCR). In some embodiments, the peptides and peptide analogues are agonists and activate the signaling pathway that is activated by the binding of the natural GCC ligands to GCC. In some embodiments, the peptides and peptide analogues block binding of natural ligands of GCC but do not activate the signaling pathway activated by the binding of the natural GCC ligands to GCC. The compounds may be used either alone or in combination with other compounds.
Guanylate Cyclase C (GCC) is a type 1 (membrane bound) guanylate cyclase. Guanylate Cyclase C receptors (GCCR) are found in a number of different tissues in the human body (Vaandrager, 2002), but it is predominately present in the gastrointestinal tract. Agonists to the human GCCR include the natural peptide hormones Guanylin and Uroguanylin, as well as a number of bacterial peptides, including the ST peptides that are produced by Escherichia coli and other bacteria (Currie et al., 1992; Tian et al., 2008; Giannella & Mann, 2003; Hamra et al., 1993; Forte, 1999; Schulz et al., 1990; Guba et al., 1996; Joo et al., 1998).
GCC regulates the fluid balance, inflammatory processes and the balance of proliferation and differentiation of the epithelium in the intestine (Evan & Vousden, 2001; Eastwood, 1992; Li et al., 2007a; Bharucha & Waldman, 2010; Sharma et al., 2010; Weiglmeier et al., 2010). The intestinal epithelium is dynamic, with a well-defined vertical axis extending from the crypt depths, in the wall of the intestine, to the tips of villi which project out into the lumen of the intestine. Epithelial cells are “born” at or near the bottom of crypts as daughter cells produced by intestinal stem cells. Recent work with lineage tracing in transgenic animals has offered evidence that—at least in the mouse intestine—cells with stem cell characteristics reside in a narrow band a few cell layers above the crypt bottom (Barker et al., 2007). These daughter cells continue to divide (proliferate), and their progeny migrates up the wall of the crypt toward the tip of the villus. Along this migration, the cells shift from proliferation to differentiation to become fully-functional mature enterocytes with the capacity to perform the normal functions of the gut including digestion, absorption and secretion. Once at the tip, these cells slough off into the lumen of the intestine and die. Thus, the intestinal epithelium turns over every three to five days. GCC and its endogenous ligands appear to be one of the factors that mirror the shift of epithelial cells from proliferation to differentiation along the crypt-villus axis. Indeed, GCC ligands inhibit the proliferation of these cells and change their gene expression pattern to a more terminally-differentiated state (Pitari et al., 2001).
The binding of endogenous (uroguanylin and guanylin) and exogenous ligands (the methanol-soluble, heat stable enterotoxins) to the extracellular domain of GCCR activates the intracellular guanylyl cyclase domain of this receptor, producing cGMP. One of the results of this increase in intracellular cGMP is activation of cGMP-dependent protein kinase (CGKII) and subsequent phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR). This phosphorylation of CFTR opens its ion channel with subsequent efflux of chloride ions from the enterocytes, followed by the passage of counterions (i.e. Na) and water into the intestinal lumen. In addition to CFTR, other transporters of electrolytes may also possibly be involved in this process, as well as other receptors (Seidler et al., 1997; Vaandrager et al., 1997).
One of the clinical manifestations of reduced CFTR activity in cystic fibrosis patients is the inflammation of airway passages. This effect may be due to CTFR regulating the expression of NF-kB, chemokines and cytokines. Recent reports have also suggested that the CFTR channel is involved in the transport and maintenance of reduced glutathione, an antioxidant that plays an important role in protecting against inflammation caused by oxidative stress (Colin-Bisello et al., 2005). Enhancement of intracellular levels of cGMP by way of guanylate cyclase C activation would be expected to down-regulate these inflammatory stimuli. Thus, GCC agonists should be useful in the prevention and treatment of inflammatory diseases of the lung (e.g., asthma), bowel (e.g., ulcerative colitis and Crohn's disease), pancreas and other organs.
Guanylin and Uroguanylin mediated signaling via cGMP is important to the normal function of the gut. Guanylin and Uroguanylin serve as paracrine regulators of GCCR activity in the intestine and therefore regulate electrolyte and fluid transport in the GI tract. Abnormalities or disturbance of this process contribute to gastrointestinal disorders such as Chronic Idiopathic Constipation (CIC), Irritable Bowel Syndrome (IBS) and Celiac disease (Collins, 2007; Ramamoorthy et al., 2007; Collins & Bercik, 2009). These receptors also influence inflammatory conditions and cell proliferation, and abnormalities in the process can also lead to conditions such as Inflammatory Bowel Disorders (IBD) or Cancers (Shailubhai et al., 2000; Shailubhai, 2002; Li et al., 2007b; Askling et al., 2001).
Chronic Idiopathic Constipation and Irritable Bowel Syndrome are disorders of the gut that are a cause of discomfort and pain. In these conditions there is no serious inflammatory involvement, although there may be a low grade of inflammation present. The pathology involves altered motility, decreased stool hydration, and visceral sensitivity. Underlying causes may include the involvement of 5-HT (5-hydroxytryptamine, serotonin), which is regulated by cGMP. An alteration in the renewal of the mucosa may also be involved along with a change in the apoptosis rate of cells in the intestinal tissue, which may also influence oncogenic processes (Carrithers, 2003; Bharucha, 2010; Lin et al, 2010). The definition and diagnosis of CIC and IBS have been established in the Rome Criteria (Drossman, 1999). CIC and IBS are classified as a functional gastrointestinal disorders, resulting from a combination of altered bowel motility and an increased visceral sensitivity. In CIC, the bowel motility is lowered and stool hydration is reduced. There are three main subgroups of IBS; constipation dominant, diarrhea dominant, or mixed which alternates between constipation and diarrhea. In all IBS conditions bowel motility is altered and there is an increased visceral sensitivity. Both CIC and IBS are very prevalent condition, affecting at least 10 million people in the United States alone.
Inflammatory Bowel Disease describes a group of disorders where the intestine is inflamed. These include Ulcerative Colitis and Crohn's disease. Ulcerative Colitis is an inflammatory disorder of the colon, although it can also appear in other sections of the intestine. Ulcerative Colitis affects only the mucosa of the intestine. Crohn's disease is a serious condition that affects mainly the colon and ileum, but it can also be found in other parts of the intestine. In Crohn's disease, all layers of the intestine are affected. Depending on the location in the intestine, Crohn's disease can also be called enteritis or colitis.
Diarrheal diseases are the fourth leading cause of mortality worldwide, responsible for about 20 million deaths each year. Such diseases are the leading cause of pediatric mortality worldwide, particularly affecting children under 5 years of age. Further, diarrheal diseases are responsible for a large part of the more prevalent growth retardation observed in children raised in developing compared to developed nations. One major cause of diarrheal disease are organisms producing heat-stable enterotoxins (STs), a family of structurally-related peptides produced by a variety of species including, but not limited to enteric bacteria such as E. coli, Yersinia, Enterobacter, and Vibrio. This family of structurally-related ST peptides is homologous to the endogenous peptides guanylin and uroguanylin produced in the mammalian intestine. ST-producing organisms are a major cause of endemic diarrhea in under-developed countries, the leading cause of travelers' diarrhea, and the leading cause of diarrheal disease in agriculturally-important animal populations (scours) in developed and under-developed countries. It is estimated that the annual incidence of ST-induced diarrheal disease numbers in the billions in animals and humans. ST induces diarrhea by binding to GCC, which is selectively expressed in the brush border membranes of intestinal epithelial cells and is the presumed receptor for the endogenous ligands guanylin and uroguanylin. Interaction of ST, or the endogenous ligands guanylin and uroguanylin, with GCC activates that receptor, resulting in the production of intracellular cyclic GMP. Cyclic GMP, through a signaling cascade, induces the secretion of salt and water into the lumen of the intestine, resulting in diarrhea. It has been suggested that one function for the endogenous ligands guanylin and uroguanylin in normal physiology is the regulation of fluid and electrolyte homeostasis in the intestine, and the hydration of intestinal contents (e.g. stool). Thus, it is possible to use analogues of ST peptides as therapeutic agents to affect the state of, or prevent, many diseases where GCC plays a role.
Overall, it may be concluded that agonists of guanylate cyclase C have potential therapeutic value in the treatment of a number of conditions, including constipation, irritable bowel syndrome, and a wide variety of inflammatory conditions, as well as potential use as anti-metastatic agents in the treatment of cancer. The development of new agonists is therefore of substantial clinical importance.
Natural GCCR Agonist Peptide Species
There are a number of different peptides with similarity to Guanylin and Uroguanylin that have been identified in different animal species, including obvious species orthologs as well as more distant homologs, but they all have significant structure and significant sequence homologies (Schulz, 1992; Krause et al., 1997; Nakazato, 2001). All mammalian Guanylins and Uroguanylins are structurally related peptides, typically 15 to 16 amino acids in length, that contain two disulphide bonds (Forte, 1999; Magert, 1998).
The amino acid sequences for the mature forms of Guanylin (Table 1A), Uroguanylin (Table 1B) in a number of vertebrate species, and of some bacterial ST peptides (Table 1C) are listed in the tables below:








TABLE 1A








Overview of Guanylin amino acid sequences












Position from N-terminus
(mature




























SEQ 
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
15
16
peptide)











Species
Genbank
ID NO
Amino acid sequence shown in publication
Publication





























Human
NP_291031.2
1
P
G
T
C
E
I
C
A
Y
A
A
C
T
G
C

Schulz, 





















1992


Chimpanzee
NW_001230449.1
2
P
G
T
C
E
I
C
A
Y
A
A
C
T
G
C




Macaque
XP_001085421.1
3
P
S
T
C
E
I
C
A
Y
A
A
C
T
G
C




Rat
CAA47901.1
4
P
N
T
C
E
I
C
A
Y
A
A
C
T
G
C




Mouse
NP_032216.1
5
P
N
T
C
E
I
C
A
Y
A
A
C
T
G
C




Pig
NP_001153746.1
6
P
S
T
C
E
I
C
A
Y
A
A
C
A
G
C




Cow
NP_001192919.1
7
P
S
T
C
E
I
C
A
Y
A
A
C
A
G
C




Sheep
EF654536.1
8
P
S
T
C
E
I
C
A
Y
A
A
C
A
G
C




Dog
NP_001185717.1
9
P
R
S
C
E
I
C
A
F
A
A
C
A
G
C




Horse
XP_001503217.1
10
P
R
M
C
E
I
C 
A
F
A
A
C
A
G
C




G. Panda
EFB17789.1
11
P
S
V
C
E
I
C
A
F
A
A
C
A
G
C




Opossum
XP_001381608.1 
12
S
H
T
C
E
I
C
A
F
A
A
C
A
G
C




Platypus
XP_001505889.1 
13
D
D
L
C
E
L
C
A
F
A
A
C
T
G
C
Y





Note:


Guanylin species contains disulphide bonds between cysteines in position 4 and 12, and between position 7 and 15.













TABLE 1B







Overview of Uroguanylin amino acid sequences














Position from N-terminus





























SEQ
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16












Species
Genbank
ID NO
Amino acid sequence shown in publication
Publication





























Human

14
N
D
D
C
E
L
C
V
N
V
A
C
T
G
C
L
Marx et al.,





















1998


Chimpanzee
XP_524686.2
15
N
D
D
C
E
L
C
V
N
V
A
C
T
G
C
L



Macaque
XP_001087987.1
16
N
D
D
C
E
L
C
V
N
V
A
C
T
G
C
L



Horse
XP_001497636.1
17
N
D
D
C
E
L
C
V
N
V
A
C
T
G
C
L



Cow
NP_001192745.1
18
N
D
D
C
E
L 
C
V
N
V
A
C
T
G
C
S



Pig
NP_001153747.1
19
G
D
D
C
E
L
C
V
N
V
A
C
T
G
C
S



Guinea p.
NP_001166429.1
20
N
D
E
C
E
L
C
V
N
I
A
C
T
G
C




Rat
NP_071620.1
21
T
D
E
C
E
L
C
I
N
V
A
C
T
G
C




Mouse
CAM14649.1
22
T
D
E
C
E
L
C
I
N
V
A
C
T
G
C




Sheep
ABR67874.1
23
D
D
D
C
E
L
C
V
N
V
A
C
T
G
C




Hopping m.
AAL77417.1
24
T
D
E
C
E
L
C
I
N
V
A
C
T
G
C




Opossum
AAB00553.1
25
Q
E
D
C
E
L
C
I
N
V
A
C
T
G
C

Virginia


Opossum
XP_001367002.1
26
Q
D
D
C
E
I
C
I
N
V
A
C
T
G
C

short tailed


Platypus
XP_001505889.1
27
N
D
D
C
E
L
C
T
N
A
A
C
T
G
C
Y





Note:


Mature Uroguanylin contains disulphide bonds between position 4 and 12, and between position 7 and 15.













TABLE 1C







Overview of ST peptide amino acid sequences












Position from N-terminus































SEQ
−1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19











Species
ID NO:
Amino acid sequence shown in publication
Publication
































E. coli STa
28

N
T
F
Y
C
C
E
L
C
C
N
P
A
C
A
G
C
Y




E. coli STp
29

N
T
F
Y
C
C
E
L
C
C
N
P
A
C
T
G
C
Y

Takao et al.,
























1983


E. coli STh
30
N
S
S
N
Y
C
C
E
L
C
C
N
P
A
C
T
G
C
Y

Nair & Takeda,
























1998


V. cholerae
31

N
T
I
D
C
C
E
I
C
C
N
P
F
C
T
G
C
L
N
Arita et al.,


n01





















1991a


Vibrio
32

N
T
I
D
C
C
E
I
C
C
N
P
F
C
T
G
C
L
N
Arita et al.,


mimicus





















1991b


V. cholerae
33

N
L
I
D
C
C
E
I
C
C
N
P
F
C
T
G
C
L
N
Takao et al.,


n01(H)





















1985a


V. Cholerae
34
G
N
L
I
D
C
C
E
I
C
C
N
P
F
C
T
G
C
L
N
Yoshino et


01





















al., 1993


Y.
35
V
S
S
D
W
D
C
D
V
C
C
N
P
A
C
T
G
C


Takao et al.,


enterocolitica





















1984


STa
























Y.
36
E
E
N
D
D
W
C
E
V
C
C
N
P
A
C
T
G
C


Takao et al.,


enterocolitica





















1985b


STb
























Y.
37
G
E
N
W
D
W
C
E
L
C
C
N
P
A
C
T
G
C


Delor et al.,


enterocolitica





















1990


STc
























Ctrobacter
38

N
N
T
T
Y
C
E
L
C
C
N
P
A
C
T
G
C


Giannella,


freundii





















1995





Table with overview of selected known ST peptide species.


Mature ST peptides have disulphide bonds between positions 5 and 10, 6 and 14, and 9 and 17.






The bacterial ST peptides are structurally different from the Guanylin and Uroguanylin peptides. These peptides are typically from 18 to 22 peptides in length, and contain three disulphide bonds (Ikemura 1984; Nair, 1998). A common core motif of all these bacterial peptides is:

N-tail-Cys-Cys-Xaa-Xaa-Cys-Cys-Xaa-Xaa-Xaa-Cys-Xaa-Xaa-Cys-C-tail Where N-tail is the N-terminal tail of the peptide, typically four to six amino acids long, and C-tail is the C-terminal tail of the peptide, typically one amino acid. Xaa can be several different amino acids. While there is some variation in the composition of the Xaa amino acids in these peptides, there is significant sequence homology between them, and the pattern of Cys-Cys-(2 amino acids)-Cyc-Cys-(3 amino acids)-Cys-(2 amino acids)-Cys is quite constant. Bacterial ST peptides are more potent stimulators of the GCCR than are Guanylin or Uroguanylin (Hamra et al., 1993; Fan et al., 1997; Hamra et al., 1997; Santos-Neto et al., 1999; Forte et al., 2000; Pitari et al., 2001). There are a number of different variants of ST peptides produced by various bacteria (Yoshimura et al., 1985). The core active sequence, i.e. the core pharmacophore, of the peptide are the 13 amino acids between the cysteine residues, i.e. the sequence Cys-Cys-Xaa-Xaa-Cys-Cys-Xaa-Xaa-Xaa-Cys-Xaa-Xaa-Cys. The activity of the ST peptide is fully retained if this structure is intact. If any of the disulphide bonds is disrupted, the activity of the peptide will be significantly degraded (Yamasaki et al., 1988; Yamasaki et al, 1988, Bull. Chem. Soc. Jpn, 61: 1701-1706), although with at least 2 of the disulphide bonds intact, the peptide can retain a portion of its activity (Tian et al., 2008) (Tian et al, 2008, Biopolymers (Pept Sci) 90: 713-723).
The ST peptide has been analyzed, and analogues have been described in a number of publications (see for instance Currie et al., 2006—WO/2006/086653; Waldman & August, 2006—U.S. Pat. No. 7,097,839; Shailubhai & Jacob, 2010—US 2010/0093635 A1). The published peptides analogues that have been made and tested involve modifications to the peptide in one of four modes: 1) Modifications using natural L-amino acids, 2) Modifications using D-amino acids, 3) Modifications to the cysteine bonds of the peptide, and 4) modifications involving conjugation of polymers to the peptide. None of these modifications have resulted in a peptide with improved properties compared to that of the basic 13 amino acid core pharmacophore, such as improved potency, stability or solubility (Tian et al., 2008).
SUMMARY OF THE INVENTION
The present invention involves compositions and related methods for treating conditions involving Guanylate Cyclase, in particular the Guanylate Cyclase C receptor (GCC), as well as conditions that respond to enhanced intracellular levels of cGMP. Intracellular levels of cGMP can be increased by enhancing the intracellular production of cGMP and/or by inhibition of its degradation by cGMP-specific enzymes such as phosphodiesterases. As described herein, the GCC is expressed on various cell types including on gastrointestinal epithelial cells, but also on cells of extra-intestinal tissues such as adrenal gland, heart, kidney, fetal liver, lung, pancreas, pituitary, and male and female reproductive tissues (Vaandrager, 2002).
The peptides of the invention may be used to treat gastrointestinal disorders including disorders involving increasing or decreasing gastrointestinal motility, inflammatory disorders, cancers, cardiac disorders, oral disorders, endocrine disorders, disorders of the lung, eye, blood, liver, prostate, and obesity. Examples of such disorders are irritable bowel syndrome (IBS), non-ulcer and functional dyspepsia, chronic intestinal and colonic pseudo-obstruction, duodenogastric and gastroesophageal reflux disease, ileus inflammation (including post-operative ileus), gastroparesis, high acidity in the GI tract, constipation including surgical constipation and constipation associated with use of medications such as opioids or osteoarthritis and osteoporosis drugs as well as constipation associated with neuropathic disorders, and Meniere's disease. Inflammatory disorders include, for instance, tissue and organ inflammation, for example kidney inflammation, gastrointestinal system inflammation including Crohn's disease and ulcerative colitis, pancreatic inflammation, lung inflammation including bronchitis or asthma, or skin inflammations such as psoriasis and eczema. Lung Disorders include chronic obstructive pulmonary disease and lung fibrosis. Cancers include tissue, organ and blood cancers and metastases such as gastrointestinal cancer, gastric cancer, and cancers of the esophagus, pancreas, colorectum, intestine, liver, gallbladder, lung, anus, thyroid, kidney, blood, skin (including melanoma), oral cavity and urinary tract. Endocrine disorders include diabetes mellitus, cystic fibrosis, hyperthyroidism, and hypothyroidism. Cardiac disorders include high cholesterol, or high triglycerides, congestive heart failure and trachea cardia hypertension. Liver disorders include cirrhosis and fibrosis and conditions associated with liver transplants. Eye disorders include glaucoma, eye inflammation, increased intra-ocular pressure, dry eyes, retinal degeneration and tear gland disorders. Skin disorders include xerosis and rosacea. Oral disorders include dry mouth, xerostomia, Sjogren's syndrome, gum diseases, periodontal disease, and salivary gland duct blockage. Prostate disorders include benign prostatic hyperplasia.
The present invention provides compounds that bind to GCC. Endogenous ligands of GCC and enterotoxins known to bind to GCC are characterized as having two or three disulphide bonds cross-linking a peptide pharmacophore with significant sequence homology. The compounds of the invention have three disulfides which cross-link a 13 amino acid pharmacophore which includes at least one non-native or isosteric amino acid substitution. The compounds of the invention bind to the GCC receptor and activate the GCC pathway. Some compounds may also bind to the GCC receptor but not activate the pathway. Some aspects of the present invention relate to these compounds and to methods of using them.
Non-limiting examples of preferred peptides included in this invention are listed below:







Peptide A (SEQ ID NO: 60):


H2N Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala


 


Gly Cys Tyr COOH


 


Peptide B (SEQ ID NO: 61):


H2N Cys Cys Glu L-Thr Cys Cys Asn Pro Ala Cys Ala


 


Gly Cys Tyr COOH


 


Peptide C (SEQ ID NO: 62):


H2N Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala


 


Gly Cys Tyr COOH


 


Peptide D (SEQ ID NO: 63):


H2N Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala


 


Gly Cys Tyr COOH






Additional preferred peptides are shown in table 3A, 3B, 3C and 8A below.




BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates threonine analogue structures that are useful substituents in the therapeutic peptides of the present invention.
FIG. 2 illustrates proline analogue structures that are useful substituents in the therapeutic peptides of the present invention.
FIG. 3 illustrates phenylalanine analogue structures that are useful substituents in the therapeutic peptides of the present invention.
FIG. 4 is a plot of GCC receptor binding activity and density in the intestine of male Sprague Dawley rats. Bmax from 1-125 ST (1-18) displacement, in Qian et al., Endocrinology 141: 3210-3224 (2000).
FIG. 5 is a plot of GCC receptor binding affinity and density in the intestine of newborn calves. Bmax from 1125 ST (1-18) displacement, (in Al-Majali et al., FEMS 28: 97-104 (2000).
FIG. 6 is a plot of GCC receptor affinity for STa (1-18) across the intestine, specifically, a plot of pKi (−log Ki) data from 1125 ST (1-18) displacement assay described in Qian et al., Endocrinology 141: 3210-3224 (2000) and Al-Majali et al., FEMS 28: 97-104 (2000). The intestine sections are those used in Qian et al., 2000.
FIG. 7 is a plot of GCC receptor Activity Induced STa (1-18) across the intestine, specifically, a plot of normalized data (percent of maximum) from intracellular cGMP accumulation, guanylyl cyclase kinetics and net fluid secretion in intestinal loop assays as described in Qian, et al, Endocrinology, 141: 3210-3224 (2000), Krause, Gut, 35: 1250 (1994) and Cohen, Am. J. Physiology, 257: G118 (1989), respectively. The intestine sections are those used in Qian et al., 2000.
FIGS. 8-a and 8b are plots of GCC receptor Activity Induced STa (1-18) across the intestine, specifically, plots of net fluid transport into ligated intestinal loops from Sprague Dawley and Wistar rats, as described in Cohen, Am. J. Physiology 257: G118 (1989) and Nzegwu, Exp. Physiology 79: 547 (1994), respectively. FIG. 8a is GCC Activation time in Sprague Dawley rats. FIG. 8b is GCC Activation time in Wistar rats.
FIG. 9 is a graphical overview of intestinal fluid volumes and transit times.
FIG. 10 is a graphical overview of the fluid regulation system in the colon where a stomach release drug is used.
FIG. 11 is a graphical overview of the fluid regulation system in the colon where a secretagogue drug released in the area between the distal jejunum, ileum, cecum and proximal colon is used.
FIG. 12 is a plot of colonic fluid content regulation with duodenal or stomach release drug.
FIG. 13 is a plot of colonic fluid content regulation with a drug that is released in the region from the distal jejunum, ileum, cecum and proximal colon.
FIG. 14 is a plot of an example formulation design profile, starting the release of the drug in the distal jejunum.
FIG. 15 is a plot of intestinal fluid flow and stool hydration control under normal and constipated conditions.
FIG. 16: is a plot illustrating intestinal fluid flow and stool hydration control where a drug is released in the stomach or duodenum.
FIG. 17 is a plot illustrating intestinal fluid flow and stool hydration control where a drug having a slow release formulation is released in the ileum.
FIG. 18 is a comparative plot of the results of an 1-125 binding assay.
FIG. 19 is a comparative plot of the results of an 1-125 binding assay.
FIG. 20 is a comparative plot of the results of an 1-125 binding assay.
FIG. 21 is a comparative plot of the results of an 1-125 binding assay.
FIG. 22 is a comparative plot of the results of a cGMP accumulation assay.
FIG. 23 is a comparative plot of the results of a cGMP accumulation assay.
FIG. 24 is a comparative plot of the results of a mouse intestinal secretion assay.
FIG. 25 is a comparative plot of the results of a mouse intestinal secretion assay.
FIG. 26 is a comparative plot of the results of a mouse intestinal secretion assay
FIG. 27 is an HPLC chromatogram of purified peptide A (SEQ ID NO: 60).
FIG. 28 is an HPLC chromatogram of purified peptide B (SEQ 1D NO: 61).
FIG. 29 is an HPLC chromatogram of purified peptide C (SEQ 1D NO: 62).
FIG. 30 is an HPLC chromatogram of purified peptide D (SEQ ID NO: 63).



DETAILED DESCRIPTION OF THE INVENTION
Terminology
As used herein, the following terms shall have the following meanings:
As used herein, the terms “antagonist”, “antagonist compounds,” “antagonists of the invention” are meant to refer to compounds which bind to GCC and block GCC binding to natural ligands but do not activate the GCC pathway.
As used herein, the terms “agonist,” “agonist compounds,” “agonists of the invention” are meant to refer to compounds which bind to GCC and block GCC binding to natural ligands and activate the GCC pathway.
As used herein, the term “natural ligands” is meant to refer to the methanol-soluble, heat stable enterotoxins as well as the endogenously produced GCC ligands guanylin and uroguanylin.
As used herein, the term “standard amino acids” means the naturally occurring 20 amino acids commonly incorporated into mammalian proteins. These 20 standard amino acids are the L-isomers of the naturally occurring amino acids, glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, carboxyglutamic acid, arginine, ornithine and lysine. Unless specifically indicated, all amino acids referred to in this application are in the L-form.
As used herein, the term “modified amino acid” (or the terms “non-natural amino acid”, or “synthetic” or “unnatural” or “non-naturally occurring” amino acid) means any amino acids other than the 20 standard amino acids listed above. In addition to the 20 standard amino acids, there are many other amino acids; these can be naturally occurring or non-natural amino acids. Some of these can be found naturally incorporated into proteins, e.g. after post-translational modification, or not (non-protein amino acids); further, they may be derived by chemical or metabolic modification of any of the standard amino acids or synthesized de novo by entirely artificial means.
Examples of naturally occurring non-standard, modified amino acids sometimes found in natural proteins are selenocysteine, pyrrolysine, hydroxyproline, selenomethionine, ornithine, taurine; examples of naturally occurring but non-protein (i.e. not usually found incorporated into natural proteins) non-standard modified amino acids are carnitine, gamma-aminobutyric acid, hypusine, L-DOPA (L-3,4-dihydroxyphenylalanine), lanthionine, 2-aminoisobutyric acid, dehydroalanine, citrulline, beta alanine (3-aminopropanoic acid). Examples of many other non-natural non-standard amino acids are given below.
As used herein, the term “derivatized amino acid” describes a native amino acid which has been chemically modified. A non-limiting example is penicillamine. There are many other non-standard amino acids—natural, derivatized or synthetic—many of which have been described in the literature (Hunt, 1985; Schultz et al., 2002; Cho et al., 2006; Konno, 2007; Muir, 2009; Alfonta et al., 2010; Currie et al., 2006; 2009; Shailubhai, 2010; Shailubhai & Jacobs, 2010; Shailubhai & Comiskey 2010-US20100221329).
As used herein, the term “treatment” refers to modifying, reducing, alleviating or eliminating symptoms in a subject, as well as preventing symptoms from occurring, worsening or progressing.
As used herein, “efficacy” of a treatment can be measured as an improvement in one or more measurements such as morbidity, mortality, symptoms severity, numbers of symptoms, or control or prevention of a disease.
As used herein, a methylated amino acid is any non-standard amino acid containing one or more methyl groups.
As used herein, the term “pegylated amino acid” shall mean any amino acid, standard or modified, that is covalently linked to one or more units of polyethylene glycol of various length (e.g. PEG 400 or PEG600) or other glycols that are liquid or solid at room temperature, or other polymeric stabilizers.
As used herein, the term “amino acid mimetic (isostere)” means an organic molecule which approximates the steric and electronic configuration of the amino acid it is intended to replace. A non-limiting example is Norleucine.
As used herein, the term “guanylate cyclase C (GCC)” is used to describe the class of guanylate cyclase C receptor on any cell type or tissue to which the agonist peptides analogues or natural agonists described herein bind. The term “intestinal guanylate cyclase receptor” as used herein describes receptors found exclusively on epithelial cells lining the intestinal mucosa. There may also be different receptors to which these agonists bind, and the receptors described herein therefore include any such receptors found on cells, tissue, or the intestinal mucosa.
As used herein, the term “GC agonist” or “GC receptor agonist” is used to describe peptides or compounds that bind to Guanylate Cyclases. The term “GCC agonist” or “GCC receptor agonist” is used to describe peptides or compounds that bind to Guanylate Cyclase C receptors, including those found on the intestinal mucosa. Such peptides may stimulate electrolyte and fluid transport. In the gastrointestinal tract they stimulate electrolyte and water secretion into the intestine. The terms as used herein also covers fragments or pre-peptides that bind to the receptors and stimulate electrolyte and fluid secretion. The term “GCC peptide” is used to describe a peptide of the invention that binds to the Guanylate Cyclase C receptor and acts as either an agonist or antagonist.
As used herein, the term “CIC” means Chronic Idiopathic Constipation.
As used herein, the term “IBS” means Irritable Bowel Syndrome, IBS-c means constipation dominant IBS, IBS-d means diarrhea dominant IBS, and IBM-m means mixed constipation and diarrhea dominant IBS. IBS may also mean pain-predominant IBS or post-infectious IBS (IBS-PI).
As used herein, the term “peptide” does not imply a molecule of particular length. In some embodiments the peptides can be between 5 and 30 amino acids in length.
The ST peptides analogues described herein bind the guanylate cyclase C receptor and stimulate intracellular production of cyclic guanosine monophosphate (cGMP). Their binding to the GCC receptor may also induce apoptosis. The ST peptide analogues may exhibit stronger binding to the GCC receptor, stimulate higher intracellular cGMP production, and stimulate more intestinal fluid production than naturally occurring GC-C agonists such as Uroguanylin, Guanylin and ST peptides. For example, the ST peptide analogues of the invention stimulate production of between 10% and 100%, or more, intracellular cGMP, as well as receptor binding or intestinal fluid production, compared to naturally occurring GC-C agonists. The peptide analogues described herein may also be more soluble than naturally occurring peptides, and more stable. The latter maybe be because the peptides described here are in some instances more slowly degraded by reductases and proteases compared to naturally occurring GCC agonists, for example between 1% and 100%, or more, than naturally occurring peptides.
The term “ST peptide analogues” used herein can describe polymers of L-amino acids, D-amino acids, non-naturally occurring amino acids, a derivatized amino acid or an amino acid mimetic, or a combination of all of these. In some embodiments, the peptides can be “retroinverso” peptides, where the direction of the sequence is reversed and the chirality of each amino acid residue is inverted (Jameson et al., 1994; Jameson & Dodson, 1994). Unless otherwise stated, it is assumed that any given L-amino acid sequence (including non-naturally occurring L-amino acid derivatives in the sequence) may be made into a D-retroinverso peptide by synthesizing a reverse of the sequence for the corresponding native L-amino acid sequence, and vice versa for D-amino acid sequences. The reverse synthesis as described here will result in a peptide where the position of the side-chain groups at each alpha carbon is preserved through the exchange of the positions of the carbonyl and the amino groups in each amide bond.
In the formulas as described herein, Xaa is any natural or unnatural, L or D amino acid or amino acid analogue. The use of D-amino acids in synthetic peptide analogues has been described in a number of publications (Konno, 2007). Non-natural amino acids include a number of different amino acid derivatives that have been described (Muir & Abelson, 2009). The cysteine and disulphide bonds in the peptide can be modified as described in a number of different publications (Gariepy et al., 1987; Shimonishi et al., 1987; Hikada et al., 1988; Yamasaki et al., 1988; Hidaka et al., 1991; Yamanaka et al., 1998)
The amino acids in ST peptides can be replaced by a naturally or non-naturally occurring L- or D-amino acid analog. There are numerous amino acids beyond the standard 20 amino acids commonly found in human proteins (Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, H is, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) (Hunt, 1985). Any amino acid can be substituted by the D-form of the amino acid. To improve the activity of the ST peptide pharmacophore, substitutions with non-naturally occurring amino acids offer the potential to enhance potency, stability and/or solubility.
Therapeutic Uses of the Compounds
Among the specific conditions that can be treated or prevented are gastrointestinal disorders, blood disorders, cancer, cardiac disorders, endocrine disorders, eye disorders, inflammatory disorders, liver disorders, lung disorders, oral and throat disorders, prostate disorders, skin disorders and obesity. Gastrointestinal disorders include for example dyspepsia; nonulcer dyspepsia; functional dyspepsia; chronic intestinal pseudo-obstruction; colonic pseudo-obstruction; duodenogastric reflux; gastroparesis; gastroesophageal reflux disease; ileus inflammation; post-operative ileus; heartburn (i.e. high acidity in the GI tract); functional heartburn; constipation, e.g., constipation associated with use of medications such as opioids, osteoarthritis drugs, osteoporosis drugs; post-surgical constipation, constipation associated with neuropathic disorders; Crohn's disease; Ulcerative colitis; irritable bowel syndrome (IBS), e.g., constipation predominant-IBS, diarrhea predominant-IBS, and/or mixed/alternating-IBS. Cardiac disorders include for example, congestive heart failure; high cholesterol; high tryglycerides; trachea cardia hypertension. Cancer includes tissue and organ carcinogenesis including metastases such as blood cancer, e.g. myeloma or leukemia; eye cancer; gastrointestinal cancer, e.g., gastric cancer, esophageal cancer, pancreatic cancer, colorectal cancer, intestinal cancer, anal cancer, liver cancer, gallbladder cancer, or colon cancer; liver cancer; lung cancer; oral cancer; skin cancer, e.g., melanoma; thyroid cancer; prostate cancer; urinary tract cancer, e.g. bladder cancer or kidney cancer. Endocrine disorders include for example cystic fibrosis; diabetes mellitus; hyperthyroidism; hypothyroidism. Eye disorders include for example dry eyes; retinal degeneration; disorders of tear glands; eye inflammation; dry eye syndrome; increased intra-ocular pressure; glaucoma; age-related macular degeneration. Inflammatory disorders include tissue and organ inflammation; lung inflammation, e.g., bronchitis or asthma; kidney inflammation, e.g., nephritis; gastrointestinal system inflammation, e.g., Crohn's disease and ulcerative colitis; necrotizing enterocolitis (NEC); pancreatic inflammation such as pancreatitis; skin inflammation (e.g., psoriasis, eczema). Kidney disorders include for example kidney cancer; kidney failure; nephritis; reflux neuropathy. Liver disorders include for example cirrhosis; fibrosis; Improvement of liver regeneration in liver transplant patients. Lung disorders include for example asthma; chronic obstructive pulmonary disease (COPD); cibrosis; cronchitis; cystic fibrosis; emphysema. Oral disorders include for example dry mouth, e.g. xerostomia; Sjogren's syndrome; salivary gland disorder, e.g. salivary gland duct blockage or malfunction; gum diseases, e.g., periodontal disease. Prostate disorders include for example benign prostatic hyperplasia (BPH); prostate cancer. Skin disorders include for example dry skin; xerosis; melanoma; psoriasis. Some compounds of the invention are useful to prevent or treat cancer (as conjugates or adjuvants to active agents), particularly metastasized colorectal cancer and primary and metastasized esophageal and stomach cancer, as well as prevent metastasis and activate the GCC pathway to induce defecation such when an individual is constipated or impacted. Some aspects of the present invention relate to these compounds and to methods of using them.
There are two compounds of the GCC agonist class that that are in clinical development at the time of the submission of this invention, linaclotide and plecanatide. Plecanatide is a Uroguanylin peptide with the sequence







SEQ ID NO: 39:


Asn Asp Glu Cys Glu Leu Cys Val Asn Val Ala Cys


 


Thr Gly Cys Leu






Linaclotide is an ST peptide analogue compound with the sequence








SEQ ID NO: 40:


Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly


 


Cys Tyr






A common reference peptide used in this specification is the E. coli STa peptide:








SEQ ID NO: 28:


Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro


 


Ala Cys Ala Gly Cys Tyr






The agonists described here are analogs of ST peptide and have superior properties such as higher potency for stimulating the GCC receptor and cGMP production than native naturally occurring ST peptides. They are also significantly more potent that Uroguanylin or Guanylin or analogues of Uroguanylin or Guanylin. They may also have high resistance to degradation by reductases present in tissues and in the intestine. The primary step for the degradation of ST peptides and reduction of their activity is reduction of the disulphide bonds by reductases (Currie et al., 1992; Okamoto et al., 1995; Hasegawa et al., 1999; Batisson et al., 2000; Kessler et al., 2008; Kessler et al., 2009).
Composition of Compounds in the Invention
The present invention relates to compositions and uses of compounds having a structure according to formula:









SEQ ID NO: 41:



H2N-Cys(1)-Cys(2)-Xaa(3)-Xaa(4)-Cys(5)-Cys(6)-



 



Xaa(7)-Xaa(8)-Xaa(9)-Cys(10)-Xaa(11)-Xaa(12)-



 



Cys(13)-COOH






Where Xaa can be several different amino acids. The numbers in parenthesis refer to the amino acids position in the peptide, starting from the N-terminus. The peptide has disulphide bonds between Cys(1) and Cys(6), Cys(2) and Cys(10), and between Cys(5) and Cys(13).

In one embodiment, the present invention relates to the composition and uses of compounds having a structure according to formula:







SEQ ID NO: 53:


H2N-X(1)-Cys(2)-Glu(3)-Z(4)-Cys(5)-Cys(6)-Asn(7)-


 


Pro(8)-Ala(9)-Cys(10)-Ala(11)-Gly(12)-Cys(13)-COOH






where X is D or L-Cysteine, or D or L-Penicillamine, and where Z is L-Leucine, L-NorLeucine, or L-Threonine. The numbers in parenthesis refers to the amino acids position in the peptide, starting from the N-terminus. The peptide has disulphide bonds between X(1) and Cys(6), Cys(2) and Cys(10), and between Cys(5) and Cys(13).

The structure is embodied by several non-limiting examples:








SEQ ID NO: 42:


L-Cys-Cys-Glu-L-Thr-Cys-Cys-Asn-Pro-Ala-Cys-Ala-


 


Gly-Cys


 


SEQ ID NO: 43:


L-Cys-Cys-Glu-L-norLeu-Cys-Cys-Asn-Pro-Ala-Cys-


 


Ala-Gly-Cys


 


SEQ ID NO: 44:


D-Cys-Cys-Glu-L-Thr-Cys-Cys-Asn-Pro-Ala-Cys-Ala-


 


Gly-Cys


 


SEQ ID NO: 45:


D-Cys-Cys-Glu-L-Leu-Cys-Cys-Asn-Pro-Ala-Cys-Ala-


 


Gly-Cys


 


SEQ ID NO: 46:


D-Cys-Cys-Glu-L-norLeu-Cys-Cys-Asn-Pro-Ala-Cys-


 


Ala-Gly-Cys


 


SEQ ID NO: 47:


D-Pen-Cys-Glu-L-Thr-Cys-Cys-Asn-Pro-Ala-Cys-Ala-


 


Gly-Cys


 


SEQ ID NO: 48:


D-Pen-Cys-Glu-L-Leu-Cys-Cys-Asn-Pro-Ala-Cys-Ala-


 


Gly-Cys


 


SEQ ID NO: 49:


D-Pen-Cys-Glu-L-norLeu-Cys-Cys-Asn-Pro-Ala-Cys-


 


Ala-Gly-Cys


 


SEQ ID NO: 50:


L-Pen-Cys-Glu-L-Thr-Cys-Cys-Asn-Pro-Ala-Cys-Ala-


 


Gly-Cys


 


SEQ ID NO: 51:


L-Pen-Cys-Glu-L-Leu-Cys-Cys-Asn-Pro-Ala-Cys-Ala-


 


Gly-Cys


 


SEQ ID NO: 52:


L-Pen-Cys-Glu-L-norLeu-Cys-Cys-Asn-Pro-Ala-Cys-


 


Ala-Gly-Cys






In one embodiment, the present invention provides a peptide comprising the sequence X-Cys-Glu-Z-Cys-Cys-Asn-Pro-Ala-Cys-Ala-Gly-Cys (SEQ ID NO: 53), where X is D or L-Cysteine, or D or L-Penicillamine, and where Z is L-Leucine, L-NorLeucine, or L-Threonine. The present invention also contemplates pharmaceutical compositions comprising these peptides. The present invention also contemplates methods of treating a gastrointestinal disease, comprising administering these peptides.
In one embodiment, the present invention provides a method of treating constipation and irritable bowel syndrome, comprising administering a peptide comprising the sequence X-Cys-Glu-Z-Cys-Cys-Asn-Pro-Ala-Cys-Ala-Gly-Cys (SEQ ID NO: 53), where X is D or L-Cysteine, or D or L-Penicillamine, and where Z is L-Leucine, L-NorLeucine, or L-Threonine. In another embodiment, the present invention provides a method of treating constipation and irritable bowel syndrome, comprising administering a peptide consisting of the sequence X-Cys-Glu-Z-Cys-Cys-Asn-Pro-Ala-Cys-Ala-Gly-Cys (SEQ ID NO: 53), where X is D or L-Cysteine, or D or L-Penicillamine, and where Z is L-Leucine, L-NorLeucine, or L-Threonine.
Scheme 1 shows the peptide sequences of the invention and the location of residues that may be modified, and exemplary modifications that may be made at each residue.










SCHEME 1









position-no.:



























1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19









Natural sequence:



























Asn
Thr
Phe
Tyr
Cys
Cys
Glu
Leu
Cys
Cys
Asn
Pro 
Ala
Cys
Ala
Gly
Cys
Tyr
Tyr





























Substi-
Ser
Ser
Tyr
Phe
Pen
Pen
Ser
Thr
Pen
Pen

Dhp

Pen
Thr
D-
Pen




tutions:















Ala






Thr
Asn

Trp
Mpr

hSer
hLeu



Thz


Ser


Phe
Phe









Csa
nor



HyPro


4F-


Ile
Ile










Leu






Phe














Chx



Pip


4MeO-


Trp
Trp










Ala






Phe














Chx



Ile


4NO2-














Ile






Phe














Phe



Ala


5F-





















Phe














Tyr






4MeF3-





















Phe














Dopa





















NMe-





















Leu
















TABLE 2





Abbreviations used in Scheme 1
















Pen =
Penicillamine


hSer =
Homoserine, Hse


Csa =
Cysteic Acid


hLeu =
Homoleucine, Hle


norLeu =
Norleucine, Nle


ChxAla =
Cyclohexyl-Aalanine, Cha


ChxIle =
Cyclohexyl-Isoleucine, Chi


Dopa =
L-Dopamine, L-dihydroxyphenylalanine


Dhp =
3,4,-dihydro-Proline, D-Pro 3,4-



Dehydroproline


Thz =
Thiazolidine (4-thiazolidine-2-carboxylic 



acid), Tzd


HyPro =
Hydroxy-Proline, Hyp, Hydroxyproline


Pip =
L-Pipecolic Acid


4F-Phe =
4-fluoro-Phenylalanine, Phe(4-F), 



4-fluorophenylalanine


4MeO-Phe =
4-methoxy-Phenylalanine, Phe(4-OMe), 



4-methoxyphenylalanine


4NO2-Phe =
4-nitro-Phenylalanine, Phe(4-NO2), 



4-Nitrophenylalanine


5F-Phe =
Pentafluoro-Phenylalanine, Phe(3-F), 



3-fluorophenylalanine


4MeF3-Phe =
Phe(4-MeF3), 4-trifluoromethyl-



phenylalanine


NMe-Leu =
N-methyl-leucine, MeLeu, N-



Methylleucine


D-Ala =
D-Alanine


Mpr =
3-mercaptoproprionic acid


▭ =
None (or deletion)





natural amino acids
(L-amino acids unless otherwise stated)





Alanine =
Ala


Arginine =
Arg


Asparagine =
Asn


Aspartic acid =
Asp


Cysteine =
Cys


Glutamic acid =
Glu


Glutamine =
Gln


Glycine =
Gly


Histidine =
His


Isoleucine =
Ile


Leucine =
Leu


Lysine =
Lys


Methionine =
Met


Phenylalanine =
Phe


Proline =
Pro


Serine =
Ser


Threonine =
Thr


Tryptophan =
Try


Tyrosine =
Tyr


Valine =
Val









Additional embodiments include but are not limited to those shown in the following Tables 3A, 3B, and 3C, showing single, double and triple substitutions that may be used in the practice of the invention. The embodiments shown in the tables are shown without the first four amino acids on the N-terminal and the C-terminal residue (i.e. residues 1-4 and 19 were left off). The amino acids shown in scheme 1 may be optionally included at these positions on the sequences shown in the tables. In one embodiment, a peptide may have the sequence Asn Thr Phe Tyr Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr Tyr (SEQ ID NO: 59). In another embodiment the peptide may have one of the following sequences:







SEQ ID NO: 60 (Peptide A):


H2N Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala


 


Gly Cys Tyr COOH


 


SEQ ID NO: 61 (Peptide B):


H2N Cys Cys Glu L-Thr Cys Cys Asn Pro Ala Cys Ala


 


Gly Cys Tyr COOH


 


SEQ ID NO: 62 (Peptide C):


H2N Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala


 


Gly Cys Tyr COOH


 


SEQ ID NO: 63 (Peptide D):


H2N Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala


 


Gly Cys Tyr COOH






In another embodiment, a peptide may have the sequence








SEQ ID NO: 64:


Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys Ala Gly


 


Cys Tyr.






In another embodiment, a peptide may have the sequence








SEQ ID NO: 65:


Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Dhp


 


Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 66:


Asn Thr Phe Tyr Cys Cys Glu L-Thr Cys Cys Asn Pro


 


Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 67:


Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn HyPro


 


Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 68:


Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Thz


 


Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 69:


Asn Thr Phe Tyr Cys Cys Glu Thr Cys Cys Asn HyPro


 


Ala Cys Ala Gly Cys Tyr













TABLE 3A





Single substitutions from Scheme 1, including N-terminal tail
















SEQ ID NO: 100
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 101
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 102
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 103
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 104
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 61
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 105
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 106
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 107
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 108
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 109
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 110
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 111
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 112
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 60
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 63
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 62
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 113
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 114
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 115
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 116
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 117
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 118
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 119
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 120
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 121
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 122
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 123
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 124
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 125
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 64
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr.


 


SEQ ID NO: 150
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 151
Asn Thr Phe Tyr Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 152
Asn Thr Phe Tyr Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 153
Asn Thr Phe Tyr Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 154
Asn Thr Phe Tyr Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 66
Asn Thr Phe Tyr Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 155
Asn Thr Phe Tyr Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 156
Asn Thr Phe Tyr Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 157
Asn Thr Phe Tyr Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 158
Asn Thr Phe Tyr Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 159
Asn Thr Phe Tyr Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 160
Asn Thr Phe Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 161
Asn Thr Phe Tyr Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 162
Asn Thr Phe Tyr Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 65
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 68
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 67
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 163
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 164
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 165
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 166
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 167
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 168
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 169
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys



Tyr


 


SEQ ID NO: 170
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys



Tyr


 


SEQ ID NO: 171
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 172
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys



Tyr


 


SEQ ID NO: 173
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 174
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 175
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 69
Asn Thr Phe Tyr Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr
















TABLE 3B





Double substitutions from Scheme 1
















SEQ ID NO: 200
Pen Cys Glu norLeu Cys Pen Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 201
Mpr Cys Ser Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 202
Mpr Cys hSer Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 203
Mpr Cys Csa Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 204
Mpr Cys Glu Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 205
Mpr Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 206
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 207
Mpr Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 208
Mpr Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 209
Mpr Cys Glu Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 210
Mpr Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 211
Mpr Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 212
Mpr Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 213
Mpr Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 214
Mpr Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 215
Mpr Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 216
Mpr Cys Glu Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 217
Mpr Cys Glu Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 218
Mpr Cys Glu Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 219
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 220
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 221
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 222
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 223
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 224
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 225
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 226
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 227
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 228
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 229
Cys Cys Ser Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 230
Cys Cys Ser hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 231
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 232
Cys Cys Ser ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 233
Cys Cys Ser ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 234
Cys Cys Ser Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 235
Cys Cys Ser Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 236
Cys Cys Ser Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 237
Cys Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 238
Cys Cys hSer Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 239
Cys Cys hSer hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 240
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 241
Cys Cys hSer ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 242
Cys Cys hSer ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 243
Cys Cys hSer Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 244
Cys Cys hSer Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 245
Cys Cys hSer Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 246
Cys Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 247
Thr Csa Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 248
Cys Cys Csa hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 249
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 250
Cys Cys Csa ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 251
Cys Cys Csa ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 252
Cys Cys Csa Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 253
Cys Cys Csa Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 254
Cys Cys Csa Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 255
Cys Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 256
Cys Cys Ser Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 257
Cys Cys Ser Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 258
Cys Cys Ser Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 259
Cys Cys Ser Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 260
Cys Cys Ser Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 261
Cys Cys Ser Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 262
Cys Cys hSer Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 263
Cys Cys hSer Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 264
Cys Cys hSer Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 265
Cys Cys hSer Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 266
Cys Cys hSer Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 267
Cys Cys hSer Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 268
Cys Cys Csa Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 269
Cys Cys Csa Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 270
Cys Cys Csa Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 271
Cys Cys Csa Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 272
Cys Cys Csa Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 273
Cys Cys Csa Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 274
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 275
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 276
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 277
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 278
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 279
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 280
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 281
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 282
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 283
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 284
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 285
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 286
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 287
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 288
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 289
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 290
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 291
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 292
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 293
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 294
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 295
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 296
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 297
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 298
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 299
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 300
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 301
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 302
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 303
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 304
Cys Cys Glu Thr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 305
Cys Cys Glu Thr Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 306
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 307
Cys Cys Glu Thr Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 308
Cys Cys Glu Thr Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 309
Cys Cys Glu Thr Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 310
Cys Cys Glu hLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 311
Cys Cys Glu hLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 312
Cys Cys Glu hLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 313
Cys Cys Glu hLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 314
Cys Cys Glu hLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 315
Cys Cys Glu hLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 316
Cys Cys Glu norLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 317
Cys Cys Glu norLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 318
Cys Cys Glu norLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 319
Cys Cys Glu norLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 320
Cys Cys Glu norLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 321
Cys Cys Glu norLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 322
Cys Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 323
Cys Cys Glu ChxAla Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 324
Cys Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 325
Cys Cys Glu ChxAla Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 326
Cys Cys Glu ChxAla Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 327
Cys Cys Glu ChxAla Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 328
Cys Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 329
Cys Cys Glu ChxIle Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 330
Cys Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 331
Cys Cys Glu ChxIle Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 332
Cys Cys Glu ChxIle Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 333
Cys Cys Glu ChxIle Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 334
Cys Cys Glu Phe Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 335
Cys Cys Glu Phe Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 336
Cys Cys Glu Phe Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 337
Cys Cys Glu Phe Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 338
Cys Cys Glu Phe Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 339
Cys Cys Glu Phe Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 340
Cys Cys Glu Tyr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 341
Cys Cys Glu Tyr Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 342
Cys Cys Glu Tyr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 343
Cys Cys Glu Tyr Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 344
Cys Cys Glu Tyr Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 345
Cys Cys Glu Tyr Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 346
Cys Cys Glu Dopa Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 347
Cys Cys Glu Dopa Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 348
Cys Cys Glu Dopa Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 349
Cys Cys Glu Dopa Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 350
Cys Cys Glu Dopa Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 351
Cys Cys Glu Dopa Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 352
Cys Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 353
Cys Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 354
Cys Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 355
Cys Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 356
Cys Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 357
Cys Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 358
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 359
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 360
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 361
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 362
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 363
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 364
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 365
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 366
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 367
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 368
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 369
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 370
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 371
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 372
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 373
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 374
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 375
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 376
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 377
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 378
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 379
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 380
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 381
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 382
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 383
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 384
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 385
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 386
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 387
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 388
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 389
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 390
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 391
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 392
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 393
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 394
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 395
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 396
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 397
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 398
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 399
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 400
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 401
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 402
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 403
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 404
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 405
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 406
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 407
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 408
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 409
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 410
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 411
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 412
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 413
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 414
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 415
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 416
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 417
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 418
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 419
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 420
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 421
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 422
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 423
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 424
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 425
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 426
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 427
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 428
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 429
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 430
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 431
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 432
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 433
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 434
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 435
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 436
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 437
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 438
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 439
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 440
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 441
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 442
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 443
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 444
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 445
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 446
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 447
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 448
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 449
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 450
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 451
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 452
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 453
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 454
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 455
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 456
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 457
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 458
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 459
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 460
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 461
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 462
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 463
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 464
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 465
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 466
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 467
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 468
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 469
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 470
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 471
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 472
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 473
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 474
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 475
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 476
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 477
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 478
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 479
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 480
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 481
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 482
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 483
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 484
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 485
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 486
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 487
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 488
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 489
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 490
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 491
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 492
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 493
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 494
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 495
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 496
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 497
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 498
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 499
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 500
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 501
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 502
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 503
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 504
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 505
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 506
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 507
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 508
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 509
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 510
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 511
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 512
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 513
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 514
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 515
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 516
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 517
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 518
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 519
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 520
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 521
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 522
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 523
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 524
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 525
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 526
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 527
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 528
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 529
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp
















TABLE 3C





Triple substitutions from Scheme 1
















SEQ ID NO: 600
Cys Cys Glu norLeu Pen Cys Asn Pro Ala Cys Ala Gly Pen Tyr


 


SEQ ID NO: 601
Mpr Cys Ser Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 602
Mpr Cys Ser hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 603
Mpr Cys Ser norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 604
Mpr Cys Ser ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 605
Mpr Cys Ser ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 606
Mpr Cys Ser Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 607
Mpr Cys Ser Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 608
Mpr Cys Ser Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 609
Mpr Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 610
Mpr Cys Ser Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 611
Mpr Cys Ser Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 612
Mpr Cys Ser Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 613
Mpr Cys Ser Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 614
Mpr Cys Ser Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 615
Mpr Cys Ser Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 616
Mpr Cys Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 617
Mpr Cys Ser Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 618
Mpr Cys Ser Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 619
Mpr Cys Ser Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 620
Mpr Cys Ser Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 621
Mpr Cys Ser Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 622
Mpr Cys Ser Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 623
Mpr Cys Ser Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 624
Mpr Cys Ser Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 625
Mpr Cys Ser Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 626
Mpr Cys hSer Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 627
Mpr Cys hSer hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 628
Mpr Cys hSer norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 629
Mpr Cys hSer ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 630
Mpr Cys hSer ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 631
Mpr Cys hSer Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 632
Mpr Cys hSer Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 633
Mpr Cys hSer Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 634
Mpr Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 635
Mpr Cys hSer Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 636
Mpr Cys hSer Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 637
Mpr Cys hSer Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 638
Mpr Cys hSer Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 639
Mpr Cys hSer Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 640
Mpr Cys hSer Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 641
Mpr Cys hSer Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 642
Mpr Cys hSer Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 643
Mpr Cys hSer Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 644
Mpr Cys hSer Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 645
Mpr Cys hSer Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 646
Mpr Cys hSer Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 647
Mpr Cys hSer Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 648
Mpr Cys hSer Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 649
Mpr Cys hSer Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 650
Mpr Cys hSer Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 651
Mpr Cys Csa Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 652
Mpr Cys Csa hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 653
Mpr Cys Csa norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 654
Mpr Cys Csa ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 655
Mpr Cys Csa ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 656
Mpr Cys Csa Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 657
Mpr Cys Csa Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 658
Mpr Cys Csa Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 659
Mpr Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 660
Mpr Cys Csa Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 661
Mpr Cys Csa Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 662
Mpr Cys Csa Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 663
Mpr Cys Csa Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 664
Mpr Cys Csa Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 665
Mpr Cys Csa Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 666
Mpr Cys Csa Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 667
Mpr Cys Csa Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 668
Mpr Cys Csa Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 669
Mpr Cys Csa Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 670
Mpr Cys Csa Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 671
Mpr Cys Csa Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 672
Mpr Cys Csa Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 673
Mpr Cys Csa Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 674
Mpr Cys Csa Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 675
Mpr Cys Csa Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 676
Mpr Cys Glu Thr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 677
Mpr Cys Glu Thr Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 678
Mpr Cys Glu Thr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 679
Mpr Cys Glu Thr Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 680
Mpr Cys Glu Thr Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 681
Mpr Cys Glu Thr Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 682
Mpr Cys Glu hLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 683
Mpr Cys Glu hLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 684
Mpr Cys Glu hLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 685
Mpr Cys Glu hLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 686
Mpr Cys Glu hLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 687
Mpr Cys Glu hLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 688
Mpr Cys Glu norLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 689
Mpr Cys Glu norLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 690
Mpr Cys Glu norLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 691
Mpr Cys Glu norLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 692
Mpr Cys Glu norLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 693
Mpr Cys Glu norLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 694
Mpr Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 695
Mpr Cys Glu ChxAla Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 696
Mpr Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 697
Mpr Cys Glu ChxAla Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 698
Mpr Cys Glu ChxAla Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 699
Mpr Cys Glu ChxAla Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 700
Mpr Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 701
Mpr Cys Glu ChxIle Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 702
Mpr Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 703
Mpr Cys Glu ChxIle Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 704
Mpr Cys Glu ChxIle Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 705
Mpr Cys Glu ChxIle Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 706
Mpr Cys Glu Phe Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 707
Mpr Cys Glu Phe Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 708
Mpr Cys Glu Phe Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 709
Mpr Cys Glu Phe Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 710
Mpr Cys Glu Phe Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 711
Mpr Cys Glu Phe Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 712
Mpr Cys Glu Tyr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 713
Mpr Cys Glu Tyr Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 714
Mpr Cys Glu Tyr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 715
Mpr Cys Glu Tyr Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 716
Mpr Cys Glu Tyr Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 717
Mpr Cys Glu Tyr Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 718
Mpr Cys Glu Dopa Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 719
Mpr Cys Glu Dopa Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 720
Mpr Cys Glu Dopa Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 721
Mpr Cys Glu Dopa Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 722
Mpr Cys Glu Dopa Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 723
Mpr Cys Glu Dopa Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 724
Mpr Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 725
Mpr Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 726
Mpr Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 727
Mpr Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 728
Mpr Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 729
Mpr Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 730
Mpr Cys Glu Thr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 731
Mpr Cys Glu Thr Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 732
Mpr Cys Glu Thr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 733
Mpr Cys Glu Thr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 734
Mpr Cys Glu Thr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 735
Mpr Cys Glu Thr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 736
Mpr Cys Glu Thr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 737
Mpr Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 738
Mpr Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 739
Mpr Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 740
Mpr Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 741
Mpr Cys Glu hLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 742
Mpr Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 743
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 744
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 745
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 746
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 747
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 748
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 749
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 750
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 751
Mpr Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 752
Mpr Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 753
Mpr Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 754
Mpr Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 755
Mpr Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 756
Mpr Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 757
Mpr Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 758
Mpr Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 759
Mpr Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 760
Mpr Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 761
Mpr Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 762
Mpr Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 763
Mpr Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 764
Mpr Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 765
Mpr Cys Glu Phe Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 766
Mpr Cys Glu Phe Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 767
Mpr Cys Glu Phe Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 768
Mpr Cys Glu Phe Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 769
Mpr Cys Glu Phe Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 770
Mpr Cys Glu Phe Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 771
Mpr Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 772
Mpr Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 773
Mpr Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 774
Mpr Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 775
Mpr Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 776
Mpr Cys Glu Tyr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 777
Mpr Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 778
Mpr Cys Glu Dopa Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 779
Mpr Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 780
Mpr Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 781
Mpr Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 782
Mpr Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 783
Mpr Cys Glu Dopa Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 784
Mpr Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 785
Mpr Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 786
Mpr Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 787
Mpr Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 788
Mpr Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 789
Mpr Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 790
Mpr Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 791
Mpr Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 792
Mpr Cys Glu Thr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 793
Mpr Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 794
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 795
Mpr Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 796
Mpr Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 797
Mpr Cys Glu Phe Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 798
Mpr Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 799
Mpr Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 800
Mpr Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 801
Mpr Cys Glu Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 802
Mpr Cys Glu Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 803
Mpr Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 804
Mpr Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 805
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 806
Mpr Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 807
Mpr Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 808
Mpr Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 809
Mpr Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 810
Mpr Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 811
Mpr Cys Glu Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 812
Mpr Cys Glu Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 813
Mpr Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 814
Mpr Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 815
Mpr Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 816
Mpr Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 817
Mpr Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 818
Mpr Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 819
Mpr Cys Glu Leu Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 820
Mpr Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 821
Mpr Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 822
Mpr Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 823
Mpr Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 824
Mpr Cys Glu Leu Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 825
Mpr Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 826
Mpr Cys Glu Leu Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 827
Mpr Cys Glu Leu Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 828
Mpr Cys Glu Leu Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 829
Mpr Cys Glu Leu Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 830
Mpr Cys Glu Leu Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 831
Mpr Cys Glu Leu Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 832
Mpr Cys Glu Leu Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 833
Mpr Cys Glu Leu Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 834
Mpr Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 835
Mpr Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 836
Mpr Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 837
Mpr Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 838
Mpr Cys Glu Leu Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 839
Mpr Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 840
Mpr Cys Glu Leu Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 841
Mpr Cys Glu Leu Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 842
Mpr Cys Glu Leu Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 843
Mpr Cys Glu Leu Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 844
Mpr Cys Glu Leu Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 845
Mpr Cys Glu Leu Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 846
Mpr Cys Glu Leu Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 847
Mpr Cys Glu Leu Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 848
Mpr Cys Glu Leu Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 849
Mpr Cys Glu Leu Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 850
Mpr Cys Glu Leu Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 851
Mpr Cys Glu Leu Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 852
Mpr Cys Glu Leu Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 853
Mpr Cys Glu Leu Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 854
Mpr Cys Glu Leu Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 855
Mpr Cys Glu Leu Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 856
Mpr Cys Glu Leu Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 857
Mpr Cys Glu Leu Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 858
Mpr Cys Glu Leu Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 859
Mpr Cys Glu Leu Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 860
Mpr Cys Glu Leu Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 861
Mpr Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 862
Mpr Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 863
Mpr Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 864
Mpr Cys Glu Leu Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 865
Mpr Cys Glu Leu Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 866
Mpr Cys Glu Leu Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 867
Mpr Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 868
Mpr Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 869
Mpr Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 870
Mpr Cys Glu Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 871
Mpr Cys Glu Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 872
Mpr Cys Glu Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 873
Mpr Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 874
Mpr Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 875
Mpr Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 876
Mpr Cys Glu Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 877
Mpr Cys Glu Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 878
Mpr Cys Glu Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 879
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 880
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 881
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 882
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 883
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 884
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 885
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 886
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 887
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 888
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 889
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 890
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 891
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 892
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 893
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 894
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 895
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 896
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 897
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 898
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 899
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 900
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 901
Mpr Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 902
Cys Cys Ser Thr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 903
Cys Cys Ser Thr Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 904
Cys Cys Ser Thr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 905
Cys Cys Ser Thr Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 906
Cys Cys Ser Thr Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 907
Cys Cys Ser Thr Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 908
Cys Cys Ser hLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 909
Cys Cys Ser hLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 910
Cys Cys Ser hLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 911
Cys Cys Ser hLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 912
Cys Cys Ser hLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 913
Cys Cys Ser hLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 914
Cys Cys Ser norLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 915
Cys Cys Ser norLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 916
Cys Cys Ser norLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 917
Cys Cys Ser norLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 918
Cys Cys Ser norLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 919
Cys Cys Ser norLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 920
Cys Cys Ser ChxAla Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 921
Cys Cys Ser ChxAla Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 922
Cys Cys Ser ChxAla Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 923
Cys Cys Ser ChxAla Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 924
Cys Cys Ser ChxAla Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 925
Cys Cys Ser ChxAla Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 926
Cys Cys Ser ChxIle Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 927
Cys Cys Ser ChxIle Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 928
Cys Cys Ser ChxIle Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 929
Cys Cys Ser ChxIle Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 930
Cys Cys Ser ChxIle Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 931
Cys Cys Ser ChxIle Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 932
Cys Cys Ser Phe Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 933
Cys Cys Ser Phe Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 934
Cys Cys Ser Phe Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 935
Cys Cys Ser Phe Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 936
Cys Cys Ser Phe Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 937
Cys Cys Ser Phe Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 938
Cys Cys Ser Tyr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 939
Cys Cys Ser Tyr Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 940
Cys Cys Ser Tyr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 941
Cys Cys Ser Tyr Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 942
Cys Cys Ser Tyr Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 943
Cys Cys Ser Tyr Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 944
Cys Cys Ser Dopa Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 945
Cys Cys Ser Dopa Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 946
Cys Cys Ser Dopa Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 947
Cys Cys Ser Dopa Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 948
Cys Cys Ser Dopa Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 949
Cys Cys Ser Dopa Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 950
Cys Cys Ser NMe-Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 951
Cys Cys Ser NMe-Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 952
Cys Cys Ser NMe-Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 953
Cys Cys Ser NMe-Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 954
Cys Cys Ser NMe-Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 955
Cys Cys Ser NMe-Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 956
Cys Cys Ser Thr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 957
Cys Cys Ser Thr Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 958
Cys Cys Ser Thr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 959
Cys Cys Ser Thr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 960
Cys Cys Ser Thr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 961
Cys Cys Ser Thr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 962
Cys Cys Ser Thr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 963
Cys Cys Ser hLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 964
Cys Cys Ser hLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 965
Cys Cys Ser hLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 966
Cys Cys Ser hLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 967
Cys Cys Ser hLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 968
Cys Cys Ser hLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 969
Cys Cys Ser hLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 970
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 971
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 972
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 973
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 974
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 975
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 976
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 977
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 978
Cys Cys Ser ChxAla Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 979
Cys Cys Ser ChxAla Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 980
Cys Cys Ser ChxAla Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 981
Cys Cys Ser ChxAla Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 982
Cys Cys Ser ChxAla Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 983
Cys Cys Ser ChxAla Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 984
Cys Cys Ser ChxIle Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 985
Cys Cys Ser ChxIle Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 986
Cys Cys Ser ChxIle Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 987
Cys Cys Ser ChxIle Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 988
Cys Cys Ser ChxIle Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 989
Cys Cys Ser ChxIle Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 990
Cys Cys Ser ChxIle Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 991
Cys Cys Ser Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 992
Cys Cys Ser Phe Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 993
Cys Cys Ser Phe Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 994
Cys Cys Ser Phe Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 995
Cys Cys Ser Phe Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 996
Cys Cys Ser Phe Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 997
Cys Cys Ser Phe Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 998
Cys Cys Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 999
Cys Cys Ser Tyr Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1000
Cys Cys Ser Tyr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1001
Cys Cys Ser Tyr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1002
Cys Cys Ser Tyr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1003
Cys Cys Ser Tyr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1004
Cys Cys Ser Tyr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1005
Cys Cys Ser Dopa Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1006
Cys Cys Ser Dopa Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1007
Cys Cys Ser Dopa Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1008
Cys Cys Ser Dopa Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1009
Cys Cys Ser Dopa Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1010
Cys Cys Ser Dopa Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1011
Cys Cys Ser Dopa Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1012
Cys Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1013
Cys Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1014
Cys Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1015
Cys Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1016
Cys Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1017
Cys Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1018
Cys Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1019
Cys Cys Ser Thr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1020
Cys Cys Ser hLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1021
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1022
Cys Cys Ser ChxAla Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1023
Cys Cys Ser ChxIle Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1024
Cys Cys Ser Phe Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1025
Cys Cys Ser Tyr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1026
Cys Cys Ser Dopa Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1027
Cys Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1028
Cys Cys Ser Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1029
Cys Cys Ser Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1030
Cys Cys Ser hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1031
Cys Cys Ser hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1032
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1033
Cys Cys Ser norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1034
Cys Cys Ser ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1035
Cys Cys Ser ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1036
Cys Cys Ser ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1037
Cys Cys Ser ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1038
Cys Cys Ser Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1039
Cys Cys Ser Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1040
Cys Cys Ser Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1041
Cys Cys Ser Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1042
Cys Cys Ser Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1043
Cys Cys Ser Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1044
Cys Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1045
Cys Cys Ser NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1046
Cys Cys hSer Thr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1047
Cys Cys hSer Thr Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1048
Cys Cys hSer Thr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1049
Cys Cys hSer Thr Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1050
Cys Cys hSer Thr Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1051
Cys Cys hSer Thr Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1052
Cys Cys hSer hLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1053
Cys Cys hSer hLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1054
Cys Cys hSer hLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1055
Cys Cys hSer hLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1056
Cys Cys hSer hLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1057
Cys Cys hSer hLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1058
Cys Cys hSer norLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1059
Cys Cys hSer norLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1060
Cys Cys hSer norLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1061
Cys Cys hSer norLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1062
Cys Cys hSer norLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1063
Cys Cys hSer norLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1064
Cys Cys hSer ChxAla Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1065
Cys Cys hSer ChxAla Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1066
Cys Cys hSer ChxAla Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1067
Cys Cys hSer ChxAla Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1068
Cys Cys hSer ChxAla Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1069
Cys Cys hSer ChxAla Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1070
Cys Cys hSer ChxIle Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1071
Cys Cys hSer ChxIle Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1072
Cys Cys hSer ChxIle Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1073
Cys Cys hSer ChxIle Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1074
Cys Cys hSer ChxIle Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1075
Cys Cys hSer ChxIle Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1076
Cys Cys hSer Phe Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1077
Cys Cys hSer Phe Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1078
Cys Cys hSer Phe Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1079
Cys Cys hSer Phe Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1080
Cys Cys hSer Phe Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1081
Cys Cys hSer Phe Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1082
Cys Cys hSer Tyr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1083
Cys Cys hSer Tyr Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1084
Cys Cys hSer Tyr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1085
Cys Cys hSer Tyr Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1086
Cys Cys hSer Tyr Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1087
Cys Cys hSer Tyr Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1088
Cys Cys hSer Dopa Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1089
Cys Cys hSer Dopa Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1090
Cys Cys hSer Dopa Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1091
Cys Cys hSer Dopa Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1092
Cys Cys hSer Dopa Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1093
Cys Cys hSer Dopa Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1094
Cys Cys hSer NMe-Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1095
Cys Cys hSer NMe-Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1096
Cys Cys hSer NMe-Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1097
Cys Cys hSer NMe-Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1098
Cys Cys hSer NMe-Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1099
Cys Cys hSer NMe-Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1100
Cys Cys hSer Thr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1101
Cys Cys hSer Thr Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1102
Cys Cys hSer Thr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1103
Cys Cys hSer Thr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1104
Cys Cys hSer Thr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1105
Cys Cys hSer Thr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1106
Cys Cys hSer Thr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1107
Cys Cys hSer hLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1108
Cys Cys hSer hLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1109
Cys Cys hSer hLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1110
Cys Cys hSer hLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1111
Cys Cys hSer hLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1112
Cys Cys hSer hLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1113
Cys Cys hSer hLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1114
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1115
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1116
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1117
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1118
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1119
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1120
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1121
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1122
Cys Cys hSer ChxAla Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1123
Cys Cys hSer ChxAla Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1124
Cys Cys hSer ChxAla Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1125
Cys Cys hSer ChxAla Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1126
Cys Cys hSer ChxAla Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1127
Cys Cys hSer ChxAla Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1128
Cys Cys hSer ChxIle Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1129
Cys Cys hSer ChxIle Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1130
Cys Cys hSer ChxIle Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1131
Cys Cys hSer ChxIle Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1132
Cys Cys hSer ChxIle Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1133
Cys Cys hSer ChxIle Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1134
Cys Cys hSer ChxIle Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1135
Cys Cys hSer Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1136
Cys Cys hSer Phe Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1137
Cys Cys hSer Phe Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1138
Cys Cys hSer Phe Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1139
Cys Cys hSer Phe Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1140
Cys Cys hSer Phe Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1141
Cys Cys hSer Phe Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1142
Cys Cys hSer Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1143
Cys Cys hSer Tyr Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1144
Cys Cys hSer Tyr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1145
Cys Cys hSer Tyr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1146
Cys Cys hSer Tyr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1147
Cys Cys hSer Tyr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1148
Cys Cys hSer Tyr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1149
Cys Cys hSer Dopa Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1150
Cys Cys hSer Dopa Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1151
Cys Cys hSer Dopa Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1152
Cys Cys hSer Dopa Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1153
Cys Cys hSer Dopa Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1154
Cys Cys hSer Dopa Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1155
Cys Cys hSer Dopa Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1156
Cys Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1157
Cys Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1158
Cys Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1159
Cys Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1160
Cys Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1161
Cys Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1162
Cys Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1163
Cys Cys hSer Thr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1164
Cys Cys hSer hLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1165
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1166
Cys Cys hSer ChxAla Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1167
Cys Cys hSer ChxIle Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1168
Cys Cys hSer Phe Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1169
Cys Cys hSer Tyr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1170
Cys Cys hSer Dopa Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1171
Cys Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1172
Cys Cys hSer Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1173
Cys Cys hSer Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1174
Cys Cys hSer hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1175
Cys Cys hSer hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1176
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1177
Cys Cys hSer norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1178
Cys Cys hSer ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1179
Cys Cys hSer ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1180
Cys Cys hSer ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1181
Cys Cys hSer ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1182
Cys Cys hSer Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1183
Cys Cys hSer Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1184
Cys Cys hSer Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1185
Cys Cys hSer Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1186
Cys Cys hSer Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1187
Cys Cys hSer Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1188
Cys Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1189
Cys Cys hSer NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1190
Cys Cys Csa Thr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1191
Cys Cys Csa Thr Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1192
Cys Cys Csa Thr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1193
Cys Cys Csa Thr Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1194
Cys Cys Csa Thr Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1195
Cys Cys Csa Thr Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1196
Cys Cys Csa hLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1197
Cys Cys Csa hLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1198
Cys Cys Csa hLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1199
Cys Cys Csa hLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1200
Cys Cys Csa hLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1201
Cys Cys Csa hLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1202
Cys Cys Csa norLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1203
Cys Cys Csa norLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1204
Cys Cys Csa norLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1205
Cys Cys Csa norLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1206
Cys Cys Csa norLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1207
Cys Cys Csa norLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1208
Cys Cys Csa ChxAla Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1209
Cys Cys Csa ChxAla Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1210
Cys Cys Csa ChxAla Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1211
Cys Cys Csa ChxAla Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1212
Cys Cys Csa ChxAla Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1213
Cys Cys Csa ChxAla Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1214
Cys Cys Csa ChxIle Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1215
Cys Cys Csa ChxIle Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1216
Cys Cys Csa ChxIle Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1217
Cys Cys Csa ChxIle Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1218
Cys Cys Csa ChxIle Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1219
Cys Cys Csa ChxIle Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1220
Cys Cys Csa Phe Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1221
Cys Cys Csa Phe Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1222
Cys Cys Csa Phe Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1223
Cys Cys Csa Phe Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1224
Cys Cys Csa Phe Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1225
Cys Cys Csa Phe Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1226
Cys Cys Csa Tyr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1227
Cys Cys Csa Tyr Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1228
Cys Cys Csa Tyr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1229
Cys Cys Csa Tyr Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1230
Cys Cys Csa Tyr Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1231
Cys Cys Csa Tyr Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1232
Cys Cys Csa Dopa Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1233
Cys Cys Csa Dopa Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1234
Cys Cys Csa Dopa Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1235
Cys Cys Csa Dopa Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1236
Cys Cys Csa Dopa Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1237
Cys Cys Csa Dopa Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1238
Cys Cys Csa NMe-Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1239
Cys Cys Csa NMe-Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1240
Cys Cys Csa NMe-Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1241
Cys Cys Csa NMe-Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1242
Cys Cys Csa NMe-Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1243
Cys Cys Csa NMe-Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 1244
Cys Cys Csa Thr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1245
Cys Cys Csa Thr Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1246
Cys Cys Csa Thr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1247
Cys Cys Csa Thr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1248
Cys Cys Csa Thr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1249
Cys Cys Csa Thr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1250
Cys Cys Csa Thr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1251
Cys Cys Csa hLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1252
Cys Cys Csa hLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1253
Cys Cys Csa hLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1254
Cys Cys Csa hLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1255
Cys Cys Csa hLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1256
Cys Cys Csa hLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1257
Cys Cys Csa hLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1258
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1259
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1260
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1261
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1262
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1263
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1264
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1265
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1266
Cys Cys Csa ChxAla Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1267
Cys Cys Csa ChxAla Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1268
Cys Cys Csa ChxAla Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1269
Cys Cys Csa ChxAla Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1270
Cys Cys Csa ChxAla Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1271
Cys Cys Csa ChxAla Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1272
Cys Cys Csa ChxIle Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1273
Cys Cys Csa ChxIle Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1274
Cys Cys Csa ChxIle Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1275
Cys Cys Csa ChxIle Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1276
Cys Cys Csa ChxIle Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1277
Cys Cys Csa ChxIle Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1278
Cys Cys Csa ChxIle Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1279
Cys Cys Csa Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1280
Cys Cys Csa Phe Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1281
Cys Cys Csa Phe Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1282
Cys Cys Csa Phe Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1283
Cys Cys Csa Phe Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1284
Cys Cys Csa Phe Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1285
Cys Cys Csa Phe Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1286
Cys Cys Csa Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1287
Cys Cys Csa Tyr Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1288
Cys Cys Csa Tyr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1289
Cys Cys Csa Tyr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1290
Cys Cys Csa Tyr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1291
Cys Cys Csa Tyr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1292
Cys Cys Csa Tyr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1293
Cys Cys Csa Dopa Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1294
Cys Cys Csa Dopa Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1295
Cys Cys Csa Dopa Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1296
Cys Cys Csa Dopa Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1297
Cys Cys Csa Dopa Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1298
Cys Cys Csa Dopa Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1299
Cys Cys Csa Dopa Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1300
Cys Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1301
Cys Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1302
Cys Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1303
Cys Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1304
Cys Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1305
Cys Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1306
Cys Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1307
Cys Cys Csa Thr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1308
Cys Cys Csa hLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1309
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1310
Cys Cys Csa ChxAla Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1311
Cys Cys Csa ChxIle Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1312
Cys Cys Csa Phe Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1313
Cys Cys Csa Tyr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1314
Cys Cys Csa Dopa Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1315
Cys Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1316
Cys Cys Csa Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1317
Cys Cys Csa Thr Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1318
Cys Cys Csa hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1319
Cys Cys Csa hLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1320
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1321
Cys Cys Csa norLeu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1322
Cys Cys Csa ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1323
Cys Cys Csa ChxAla Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1324
Cys Cys Csa ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1325
Cys Cys Csa ChxIle Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1326
Cys Cys Csa Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1327
Cys Cys Csa Phe Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1328
Cys Cys Csa Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1329
Cys Cys Csa Tyr Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1330
Cys Cys Csa Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1331
Cys Cys Csa Dopa Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1332
Cys Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1333
Cys Cys Csa NMe-Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1334
Cys Cys Ser Leu Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1335
Cys Cys Ser Leu Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1336
Cys Cys Ser Leu Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1337
Cys Cys Ser Leu Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1338
Cys Cys Ser Leu Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1339
Cys Cys Ser Leu Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1340
Cys Cys Ser Leu Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1341
Cys Cys Ser Leu Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1342
Cys Cys Ser Leu Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1343
Cys Cys Ser Leu Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1344
Cys Cys Ser Leu Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1345
Cys Cys Ser Leu Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1346
Cys Cys Ser Leu Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1347
Cys Cys Ser Leu Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1348
Cys Cys Ser Leu Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1349
Cys Cys Ser Leu Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1350
Cys Cys Ser Leu Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1351
Cys Cys Ser Leu Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1352
Cys Cys Ser Leu Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1353
Cys Cys Ser Leu Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1354
Cys Cys Ser Leu Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1355
Cys Cys Ser Leu Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1356
Cys Cys Ser Leu Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1357
Cys Cys Ser Leu Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1358
Cys Cys Ser Leu Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1359
Cys Cys Ser Leu Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1360
Cys Cys Ser Leu Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1361
Cys Cys Ser Leu Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1362
Cys Cys Ser Leu Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1363
Cys Cys Ser Leu Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1364
Cys Cys Ser Leu Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1365
Cys Cys Ser Leu Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1366
Cys Cys Ser Leu Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1367
Cys Cys Ser Leu Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1368
Cys Cys Ser Leu Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1369
Cys Cys Ser Leu Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1370
Cys Cys Ser Leu Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1371
Cys Cys Ser Leu Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1372
Cys Cys Ser Leu Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1373
Cys Cys Ser Leu Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1374
Cys Cys Ser Leu Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1375
Cys Cys Ser Leu Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1376
Cys Cys Ser Leu Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1377
Cys Cys Ser Leu Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1378
Cys Cys Ser Leu Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1379
Cys Cys Ser Leu Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1380
Cys Cys Ser Leu Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1381
Cys Cys Ser Leu Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1382
Cys Cys Ser Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1383
Cys Cys Ser Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1384
Cys Cys Ser Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1385
Cys Cys Ser Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1386
Cys Cys Ser Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1387
Cys Cys Ser Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1388
Cys Cys Ser Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1389
Cys Cys Ser Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1390
Cys Cys Ser Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1391
Cys Cys Ser Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1392
Cys Cys Ser Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1393
Cys Cys Ser Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1394
Cys Cys hSer Leu Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1395
Cys Cys hSer Leu Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1396
Cys Cys hSer Leu Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1397
Cys Cys hSer Leu Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1398
Cys Cys hSer Leu Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1399
Cys Cys hSer Leu Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1400
Cys Cys hSer Leu Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1401
Cys Cys hSer Leu Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1402
Cys Cys hSer Leu Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1403
Cys Cys hSer Leu Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1404
Cys Cys hSer Leu Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1405
Cys Cys hSer Leu Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1406
Cys Cys hSer Leu Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1407
Cys Cys hSer Leu Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1408
Cys Cys hSer Leu Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1409
Cys Cys hSer Leu Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1410
Cys Cys hSer Leu Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1411
Cys Cys hSer Leu Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1412
Cys Cys hSer Leu Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1413
Cys Cys hSer Leu Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1414
Cys Cys hSer Leu Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1415
Cys Cys hSer Leu Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1416
Cys Cys hSer Leu Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1417
Cys Cys hSer Leu Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1418
Cys Cys hSer Leu Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1419
Cys Cys hSer Leu Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1420
Cys Cys hSer Leu Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1421
Cys Cys hSer Leu Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1422
Cys Cys hSer Leu Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1423
Cys Cys hSer Leu Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1424
Cys Cys hSer Leu Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1425
Cys Cys hSer Leu Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1426
Cys Cys hSer Leu Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1427
Cys Cys hSer Leu Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1428
Cys Cys hSer Leu Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1429
Cys Cys hSer Leu Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1430
Cys Cys hSer Leu Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1431
Cys Cys hSer Leu Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1432
Cys Cys hSer Leu Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1433
Cys Cys hSer Leu Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1434
Cys Cys hSer Leu Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1435
Cys Cys hSer Leu Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1436
Cys Cys hSer Leu Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1437
Cys Cys hSer Leu Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1438
Cys Cys hSer Leu Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1439
Cys Cys hSer Leu Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1440
Cys Cys hSer Leu Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1441
Cys Cys hSer Leu Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1442
Cys Cys hSer Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1443
Cys Cys hSer Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1444
Cys Cys hSer Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1445
Cys Cys hSer Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1446
Cys Cys hSer Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1447
Cys Cys hSer Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1448
Cys Cys hSer Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1449
Cys Cys hSer Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1450
Cys Cys hSer Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1451
Cys Cys hSer Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1452
Cys Cys hSer Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1453
Cys Cys hSer Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1454
Cys Cys Csa Leu Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1455
Cys Cys Csa Leu Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1456
Cys Cys Csa Leu Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1457
Cys Cys Csa Leu Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1458
Cys Cys Csa Leu Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1459
Cys Cys Csa Leu Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1460
Cys Cys Csa Leu Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1461
Cys Cys Csa Leu Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1462
Cys Cys Csa Leu Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1463
Cys Cys Csa Leu Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1464
Cys Cys Csa Leu Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1465
Cys Cys Csa Leu Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1466
Cys Cys Csa Leu Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1467
Cys Cys Csa Leu Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1468
Cys Cys Csa Leu Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1469
Cys Cys Csa Leu Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1470
Cys Cys Csa Leu Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1471
Cys Cys Csa Leu Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1472
Cys Cys Csa Leu Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1473
Cys Cys Csa Leu Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1474
Cys Cys Csa Leu Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1475
Cys Cys Csa Leu Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1476
Cys Cys Csa Leu Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1477
Cys Cys Csa Leu Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1478
Cys Cys Csa Leu Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1479
Cys Cys Csa Leu Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1480
Cys Cys Csa Leu Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1481
Cys Cys Csa Leu Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1482
Cys Cys Csa Leu Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1483
Cys Cys Csa Leu Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1484
Cys Cys Csa Leu Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1485
Cys Cys Csa Leu Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1486
Cys Cys Csa Leu Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1487
Cys Cys Csa Leu Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1488
Cys Cys Csa Leu Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1489
Cys Cys Csa Leu Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1490
Cys Cys Csa Leu Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1491
Cys Cys Csa Leu Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1492
Cys Cys Csa Leu Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1493
Cys Cys Csa Leu Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1494
Cys Cys Csa Leu Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1495
Cys Cys Csa Leu Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1496
Cys Cys Csa Leu Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1497
Cys Cys Csa Leu Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1498
Cys Cys Csa Leu Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1499
Cys Cys Csa Leu Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1500
Cys Cys Csa Leu Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1501
Cys Cys Csa Leu Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1502
Cys Cys Csa Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1503
Cys Cys Csa Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1504
Cys Cys Csa Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1505
Cys Cys Csa Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1506
Cys Cys Csa Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1507
Cys Cys Csa Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1508
Cys Cys Csa Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1509
Cys Cys Csa Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1510
Cys Cys Csa Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1511
Cys Cys Csa Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1512
Cys Cys Csa Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1513
Cys Cys Csa Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1514
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 1515
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 1516
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1517
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1518
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1519
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1520
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1521
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 1522
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 1523
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 1524
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 1525
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 1526
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 1527
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 1528
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 1529
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 1530
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 1531
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 1532
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 1533
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 1534
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 1535
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 1536
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 1537
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1538
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1539
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1540
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1541
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1542
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 1543
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 1544
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 1545
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 1546
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 1547
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 1548
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 1549
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 1550
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 1551
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 1552
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 1553
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 1554
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 1555
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 1556
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 1557
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 1558
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1559
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1560
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1561
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1562
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 1563
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 1564
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 1565
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 1566
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 1567
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 1568
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 1569
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 1570
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 1571
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 1572
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 1573
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 1574
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 1575
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 1576
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 1577
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 1578
Cys Cys Ser Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 1579
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 1580
Cys Cys hSer Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 1581
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 1582
Cys Cys Csa Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 1583
Cys Cys Glu Thr Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1584
Cys Cys Glu Thr Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1585
Cys Cys Glu Thr Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1586
Cys Cys Glu Thr Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1587
Cys Cys Glu Thr Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1588
Cys Cys Glu Thr Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1589
Cys Cys Glu Thr Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1590
Cys Cys Glu Thr Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1591
Cys Cys Glu Thr Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1592
Cys Cys Glu Thr Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1593
Cys Cys Glu Thr Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1594
Cys Cys Glu Thr Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1595
Cys Cys Glu Thr Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1596
Cys Cys Glu Thr Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1597
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1598
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1599
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1600
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1601
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1602
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1603
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1604
Cys Cys Glu Thr Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1605
Cys Cys Glu Thr Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1606
Cys Cys Glu Thr Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1607
Cys Cys Glu Thr Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1608
Cys Cys Glu Thr Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1609
Cys Cys Glu Thr Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1610
Cys Cys Glu Thr Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1611
Cys Cys Glu Thr Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1612
Cys Cys Glu Thr Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1613
Cys Cys Glu Thr Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1614
Cys Cys Glu Thr Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1615
Cys Cys Glu Thr Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1616
Cys Cys Glu Thr Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1617
Cys Cys Glu Thr Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1618
Cys Cys Glu Thr Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1619
Cys Cys Glu Thr Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1620
Cys Cys Glu Thr Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1621
Cys Cys Glu Thr Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1622
Cys Cys Glu Thr Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1623
Cys Cys Glu Thr Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1624
Cys Cys Glu Thr Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1625
Cys Cys Glu Thr Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1626
Cys Cys Glu Thr Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1627
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1628
Cys Cys Glu Thr Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1629
Cys Cys Glu Thr Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1630
Cys Cys Glu Thr Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1631
Cys Cys Glu Thr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1632
Cys Cys Glu Thr Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1633
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1634
Cys Cys Glu Thr Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1635
Cys Cys Glu Thr Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1636
Cys Cys Glu Thr Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1637
Cys Cys Glu Thr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1638
Cys Cys Glu Thr Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1639
Cys Cys Glu Thr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1640
Cys Cys Glu Thr Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1641
Cys Cys Glu Thr Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1642
Cys Cys Glu Thr Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1643
Cys Cys Glu hLeu Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1644
Cys Cys Glu hLeu Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1645
Cys Cys Glu hLeu Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1646
Cys Cys Glu hLeu Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1647
Cys Cys Glu hLeu Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1648
Cys Cys Glu hLeu Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1649
Cys Cys Glu hLeu Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1650
Cys Cys Glu hLeu Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1651
Cys Cys Glu hLeu Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1652
Cys Cys Glu hLeu Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1653
Cys Cys Glu hLeu Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1654
Cys Cys Glu hLeu Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1655
Cys Cys Glu hLeu Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1656
Cys Cys Glu hLeu Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1657
Cys Cys Glu hLeu Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1658
Cys Cys Glu hLeu Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1659
Cys Cys Glu hLeu Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1660
Cys Cys Glu hLeu Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1661
Cys Cys Glu hLeu Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1662
Cys Cys Glu hLeu Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1663
Cys Cys Glu hLeu Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1664
Cys Cys Glu hLeu Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1665
Cys Cys Glu hLeu Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1666
Cys Cys Glu hLeu Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1667
Cys Cys Glu hLeu Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1668
Cys Cys Glu hLeu Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1669
Cys Cys Glu hLeu Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1670
Cys Cys Glu hLeu Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1671
Cys Cys Glu hLeu Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1672
Cys Cys Glu hLeu Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1673
Cys Cys Glu hLeu Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1674
Cys Cys Glu hLeu Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1675
Cys Cys Glu hLeu Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1676
Cys Cys Glu hLeu Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1677
Cys Cys Glu hLeu Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1678
Cys Cys Glu hLeu Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1679
Cys Cys Glu hLeu Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1680
Cys Cys Glu hLeu Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1681
Cys Cys Glu hLeu Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1682
Cys Cys Glu hLeu Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1683
Cys Cys Glu hLeu Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1684
Cys Cys Glu hLeu Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1685
Cys Cys Glu hLeu Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1686
Cys Cys Glu hLeu Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1687
Cys Cys Glu hLeu Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1688
Cys Cys Glu hLeu Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1689
Cys Cys Glu hLeu Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1690
Cys Cys Glu hLeu Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1691
Cys Cys Glu hLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1692
Cys Cys Glu hLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1693
Cys Cys Glu hLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1694
Cys Cys Glu hLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1695
Cys Cys Glu hLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1696
Cys Cys Glu hLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1697
Cys Cys Glu hLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1698
Cys Cys Glu hLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1699
Cys Cys Glu hLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1700
Cys Cys Glu hLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1701
Cys Cys Glu hLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1702
Cys Cys Glu hLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1703
Cys Cys Glu norLeu Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1704
Cys Cys Glu norLeu Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1705
Cys Cys Glu norLeu Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1706
Cys Cys Glu norLeu Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1707
Cys Cys Glu norLeu Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1708
Cys Cys Glu norLeu Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1709
Cys Cys Glu norLeu Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1710
Cys Cys Glu norLeu Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1711
Cys Cys Glu norLeu Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1712
Cys Cys Glu norLeu Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1713
Cys Cys Glu norLeu Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1714
Cys Cys Glu norLeu Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1715
Cys Cys Glu norLeu Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1716
Cys Cys Glu norLeu Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1717
Cys Cys Glu norLeu Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1718
Cys Cys Glu norLeu Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1719
Cys Cys Glu norLeu Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1720
Cys Cys Glu norLeu Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1721
Cys Cys Glu norLeu Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1722
Cys Cys Glu norLeu Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1723
Cys Cys Glu norLeu Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1724
Cys Cys Glu norLeu Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1725
Cys Cys Glu norLeu Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1726
Cys Cys Glu norLeu Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1727
Cys Cys Glu norLeu Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1728
Cys Cys Glu norLeu Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1729
Cys Cys Glu norLeu Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1730
Cys Cys Glu norLeu Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1731
Cys Cys Glu norLeu Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1732
Cys Cys Glu norLeu Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1733
Cys Cys Glu norLeu Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1734
Cys Cys Glu norLeu Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1735
Cys Cys Glu norLeu Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1736
Cys Cys Glu norLeu Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1737
Cys Cys Glu norLeu Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1738
Cys Cys Glu norLeu Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1739
Cys Cys Glu norLeu Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1740
Cys Cys Glu norLeu Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1741
Cys Cys Glu norLeu Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1742
Cys Cys Glu norLeu Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1743
Cys Cys Glu norLeu Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1744
Cys Cys Glu norLeu Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1745
Cys Cys Glu norLeu Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1746
Cys Cys Glu norLeu Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1747
Cys Cys Glu norLeu Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1748
Cys Cys Glu norLeu Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1749
Cys Cys Glu norLeu Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1750
Cys Cys Glu norLeu Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1751
Cys Cys Glu norLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1752
Cys Cys Glu norLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1753
Cys Cys Glu norLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1754
Cys Cys Glu norLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1755
Cys Cys Glu norLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1756
Cys Cys Glu norLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1757
Cys Cys Glu norLeu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1758
Cys Cys Glu norLeu Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1759
Cys Cys Glu norLeu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1760
Cys Cys Glu norLeu Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1761
Cys Cys Glu norLeu Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1762
Cys Cys Glu norLeu Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1763
Cys Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1764
Cys Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1765
Cys Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1766
Cys Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1767
Cys Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1768
Cys Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1769
Cys Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1770
Cys Cys Glu ChxAla Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1771
Cys Cys Glu ChxAla Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1772
Cys Cys Glu ChxAla Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1773
Cys Cys Glu ChxAla Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1774
Cys Cys Glu ChxAla Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1775
Cys Cys Glu ChxAla Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1776
Cys Cys Glu ChxAla Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1777
Cys Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1778
Cys Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1779
Cys Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1780
Cys Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1781
Cys Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1782
Cys Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1783
Cys Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1784
Cys Cys Glu ChxAla Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1785
Cys Cys Glu ChxAla Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1786
Cys Cys Glu ChxAla Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1787
Cys Cys Glu ChxAla Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1788
Cys Cys Glu ChxAla Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1789
Cys Cys Glu ChxAla Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1790
Cys Cys Glu ChxAla Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1791
Cys Cys Glu ChxAla Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1792
Cys Cys Glu ChxAla Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1793
Cys Cys Glu ChxAla Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1794
Cys Cys Glu ChxAla Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1795
Cys Cys Glu ChxAla Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1796
Cys Cys Glu ChxAla Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1797
Cys Cys Glu ChxAla Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1798
Cys Cys Glu ChxAla Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1799
Cys Cys Glu ChxAla Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1800
Cys Cys Glu ChxAla Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1801
Cys Cys Glu ChxAla Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1802
Cys Cys Glu ChxAla Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1803
Cys Cys Glu ChxAla Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1804
Cys Cys Glu ChxAla Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1805
Cys Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1806
Cys Cys Glu ChxAla Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1807
Cys Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1808
Cys Cys Glu ChxAla Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1809
Cys Cys Glu ChxAla Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1810
Cys Cys Glu ChxAla Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1811
Cys Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1812
Cys Cys Glu ChxAla Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1813
Cys Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1814
Cys Cys Glu ChxAla Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1815
Cys Cys Glu ChxAla Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1816
Cys Cys Glu ChxAla Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1817
Cys Cys Glu ChxAla Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1818
Cys Cys Glu ChxAla Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1819
Cys Cys Glu ChxAla Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1820
Cys Cys Glu ChxAla Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1821
Cys Cys Glu ChxAla Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1822
Cys Cys Glu ChxAla Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1823
Cys Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1824
Cys Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1825
Cys Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1826
Cys Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1827
Cys Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1828
Cys Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1829
Cys Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1830
Cys Cys Glu ChxIle Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1831
Cys Cys Glu ChxIle Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1832
Cys Cys Glu ChxIle Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1833
Cys Cys Glu ChxIle Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1834
Cys Cys Glu ChxIle Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1835
Cys Cys Glu ChxIle Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1836
Cys Cys Glu ChxIle Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1837
Cys Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1838
Cys Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1839
Cys Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1840
Cys Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1841
Cys Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1842
Cys Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1843
Cys Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1844
Cys Cys Glu ChxIle Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1845
Cys Cys Glu ChxIle Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1846
Cys Cys Glu ChxIle Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1847
Cys Cys Glu ChxIle Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1848
Cys Cys Glu ChxIle Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1849
Cys Cys Glu ChxIle Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1850
Cys Cys Glu ChxIle Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1851
Cys Cys Glu ChxIle Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1852
Cys Cys Glu ChxIle Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1853
Cys Cys Glu ChxIle Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1854
Cys Cys Glu ChxIle Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1855
Cys Cys Glu ChxIle Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1856
Cys Cys Glu ChxIle Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1857
Cys Cys Glu ChxIle Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1858
Cys Cys Glu ChxIle Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1859
Cys Cys Glu ChxIle Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1860
Cys Cys Glu ChxIle Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1861
Cys Cys Glu ChxIle Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1862
Cys Cys Glu ChxIle Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1863
Cys Cys Glu ChxIle Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1864
Cys Cys Glu ChxIle Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1865
Cys Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1866
Cys Cys Glu ChxIle Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1867
Cys Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1868
Cys Cys Glu ChxIle Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1869
Cys Cys Glu ChxIle Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1870
Cys Cys Glu ChxIle Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1871
Cys Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1872
Cys Cys Glu ChxIle Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1873
Cys Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1874
Cys Cys Glu ChxIle Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1875
Cys Cys Glu ChxIle Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1876
Cys Cys Glu ChxIle Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1877
Cys Cys Glu ChxIle Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1878
Cys Cys Glu ChxIle Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1879
Cys Cys Glu ChxIle Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1880
Cys Cys Glu ChxIle Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1881
Cys Cys Glu ChxIle Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1882
Cys Cys Glu ChxIle Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1883
Cys Cys Glu Phe Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1884
Cys Cys Glu Phe Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1885
Cys Cys Glu Phe Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1886
Cys Cys Glu Phe Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1887
Cys Cys Glu Phe Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1888
Cys Cys Glu Phe Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1889
Cys Cys Glu Phe Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1890
Cys Cys Glu Phe Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1891
Cys Cys Glu Phe Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1892
Cys Cys Glu Phe Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1893
Cys Cys Glu Phe Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1894
Cys Cys Glu Phe Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1895
Cys Cys Glu Phe Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1896
Cys Cys Glu Phe Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1897
Cys Cys Glu Phe Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1898
Cys Cys Glu Phe Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1899
Cys Cys Glu Phe Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1900
Cys Cys Glu Phe Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1901
Cys Cys Glu Phe Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1902
Cys Cys Glu Phe Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1903
Cys Cys Glu Phe Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1904
Cys Cys Glu Phe Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1905
Cys Cys Glu Phe Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1906
Cys Cys Glu Phe Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1907
Cys Cys Glu Phe Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1908
Cys Cys Glu Phe Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1909
Cys Cys Glu Phe Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1910
Cys Cys Glu Phe Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1911
Cys Cys Glu Phe Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1912
Cys Cys Glu Phe Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1913
Cys Cys Glu Phe Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1914
Cys Cys Glu Phe Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1915
Cys Cys Glu Phe Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1916
Cys Cys Glu Phe Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1917
Cys Cys Glu Phe Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1918
Cys Cys Glu Phe Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1919
Cys Cys Glu Phe Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1920
Cys Cys Glu Phe Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1921
Cys Cys Glu Phe Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1922
Cys Cys Glu Phe Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1923
Cys Cys Glu Phe Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1924
Cys Cys Glu Phe Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1925
Cys Cys Glu Phe Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1926
Cys Cys Glu Phe Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1927
Cys Cys Glu Phe Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1928
Cys Cys Glu Phe Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1929
Cys Cys Glu Phe Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1930
Cys Cys Glu Phe Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1931
Cys Cys Glu Phe Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1932
Cys Cys Glu Phe Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1933
Cys Cys Glu Phe Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1934
Cys Cys Glu Phe Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1935
Cys Cys Glu Phe Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1936
Cys Cys Glu Phe Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1937
Cys Cys Glu Phe Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1938
Cys Cys Glu Phe Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1939
Cys Cys Glu Phe Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1940
Cys Cys Glu Phe Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1941
Cys Cys Glu Phe Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1942
Cys Cys Glu Phe Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1943
Cys Cys Glu Tyr Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1944
Cys Cys Glu Tyr Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1945
Cys Cys Glu Tyr Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1946
Cys Cys Glu Tyr Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1947
Cys Cys Glu Tyr Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1948
Cys Cys Glu Tyr Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1949
Cys Cys Glu Tyr Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1950
Cys Cys Glu Tyr Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1951
Cys Cys Glu Tyr Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1952
Cys Cys Glu Tyr Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1953
Cys Cys Glu Tyr Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1954
Cys Cys Glu Tyr Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1955
Cys Cys Glu Tyr Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1956
Cys Cys Glu Tyr Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1957
Cys Cys Glu Tyr Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1958
Cys Cys Glu Tyr Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1959
Cys Cys Glu Tyr Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1960
Cys Cys Glu Tyr Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1961
Cys Cys Glu Tyr Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1962
Cys Cys Glu Tyr Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1963
Cys Cys Glu Tyr Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1964
Cys Cys Glu Tyr Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1965
Cys Cys Glu Tyr Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1966
Cys Cys Glu Tyr Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1967
Cys Cys Glu Tyr Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1968
Cys Cys Glu Tyr Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1969
Cys Cys Glu Tyr Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1970
Cys Cys Glu Tyr Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1971
Cys Cys Glu Tyr Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1972
Cys Cys Glu Tyr Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1973
Cys Cys Glu Tyr Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1974
Cys Cys Glu Tyr Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1975
Cys Cys Glu Tyr Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1976
Cys Cys Glu Tyr Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1977
Cys Cys Glu Tyr Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1978
Cys Cys Glu Tyr Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 1979
Cys Cys Glu Tyr Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 1980
Cys Cys Glu Tyr Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 1981
Cys Cys Glu Tyr Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 1982
Cys Cys Glu Tyr Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 1983
Cys Cys Glu Tyr Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 1984
Cys Cys Glu Tyr Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 1985
Cys Cys Glu Tyr Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1986
Cys Cys Glu Tyr Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1987
Cys Cys Glu Tyr Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1988
Cys Cys Glu Tyr Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1989
Cys Cys Glu Tyr Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1990
Cys Cys Glu Tyr Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 1991
Cys Cys Glu Tyr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1992
Cys Cys Glu Tyr Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1993
Cys Cys Glu Tyr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1994
Cys Cys Glu Tyr Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1995
Cys Cys Glu Tyr Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1996
Cys Cys Glu Tyr Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 1997
Cys Cys Glu Tyr Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1998
Cys Cys Glu Tyr Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 1999
Cys Cys Glu Tyr Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2000
Cys Cys Glu Tyr Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2001
Cys Cys Glu Tyr Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2002
Cys Cys Glu Tyr Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2003
Cys Cys Glu Dopa Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2004
Cys Cys Glu Dopa Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2005
Cys Cys Glu Dopa Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2006
Cys Cys Glu Dopa Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2007
Cys Cys Glu Dopa Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2008
Cys Cys Glu Dopa Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2009
Cys Cys Glu Dopa Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2010
Cys Cys Glu Dopa Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2011
Cys Cys Glu Dopa Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2012
Cys Cys Glu Dopa Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2013
Cys Cys Glu Dopa Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2014
Cys Cys Glu Dopa Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2015
Cys Cys Glu Dopa Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2016
Cys Cys Glu Dopa Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2017
Cys Cys Glu Dopa Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2018
Cys Cys Glu Dopa Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2019
Cys Cys Glu Dopa Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2020
Cys Cys Glu Dopa Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2021
Cys Cys Glu Dopa Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2022
Cys Cys Glu Dopa Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2023
Cys Cys Glu Dopa Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2024
Cys Cys Glu Dopa Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2025
Cys Cys Glu Dopa Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2026
Cys Cys Glu Dopa Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2027
Cys Cys Glu Dopa Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2028
Cys Cys Glu Dopa Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2029
Cys Cys Glu Dopa Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2030
Cys Cys Glu Dopa Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2031
Cys Cys Glu Dopa Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2032
Cys Cys Glu Dopa Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2033
Cys Cys Glu Dopa Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2034
Cys Cys Glu Dopa Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2035
Cys Cys Glu Dopa Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2036
Cys Cys Glu Dopa Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2037
Cys Cys Glu Dopa Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2038
Cys Cys Glu Dopa Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2039
Cys Cys Glu Dopa Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2040
Cys Cys Glu Dopa Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2041
Cys Cys Glu Dopa Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2042
Cys Cys Glu Dopa Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2043
Cys Cys Glu Dopa Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2044
Cys Cys Glu Dopa Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2045
Cys Cys Glu Dopa Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2046
Cys Cys Glu Dopa Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2047
Cys Cys Glu Dopa Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2048
Cys Cys Glu Dopa Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2049
Cys Cys Glu Dopa Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2050
Cys Cys Glu Dopa Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2051
Cys Cys Glu Dopa Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2052
Cys Cys Glu Dopa Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2053
Cys Cys Glu Dopa Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2054
Cys Cys Glu Dopa Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2055
Cys Cys Glu Dopa Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2056
Cys Cys Glu Dopa Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2057
Cys Cys Glu Dopa Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2058
Cys Cys Glu Dopa Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2059
Cys Cys Glu Dopa Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2060
Cys Cys Glu Dopa Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2061
Cys Cys Glu Dopa Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2062
Cys Cys Glu Dopa Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2063
Cys Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2064
Cys Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2065
Cys Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2066
Cys Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2067
Cys Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2068
Cys Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2069
Cys Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2070
Cys Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2071
Cys Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2072
Cys Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2073
Cys Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2074
Cys Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2075
Cys Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2076
Cys Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2077
Cys Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2078
Cys Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2079
Cys Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2080
Cys Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2081
Cys Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2082
Cys Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2083
Cys Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2084
Cys Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2085
Cys Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2086
Cys Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2087
Cys Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2088
Cys Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2089
Cys Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2090
Cys Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2091
Cys Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2092
Cys Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2093
Cys Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2094
Cys Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2095
Cys Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2096
Cys Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2097
Cys Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2098
Cys Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys Thr Gly Cys Tyr


 


SEQ ID NO: 2099
Cys Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys Ser Gly Cys Tyr


 


SEQ ID NO: 2100
Cys Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Tyr


 


SEQ ID NO: 2101
Cys Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Tyr


 


SEQ ID NO: 2102
Cys Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Tyr


 


SEQ ID NO: 2103
Cys Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Tyr


 


SEQ ID NO: 2104
Cys Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Tyr


 


SEQ ID NO: 2105
Cys Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2106
Cys Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2107
Cys Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2108
Cys Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2109
Cys Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2110
Cys Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Tyr


 


SEQ ID NO: 2111
Cys Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2112
Cys Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2113
Cys Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2114
Cys Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2115
Cys Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2116
Cys Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Ile


 


SEQ ID NO: 2117
Cys Cys Glu NMe-Leu Cys Cys Asn Dhp Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2118
Cys Cys Glu NMe-Leu Cys Cys Asn Thz Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2119
Cys Cys Glu NMe-Leu Cys Cys Asn HyPro Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2120
Cys Cys Glu NMe-Leu Cys Cys Asn Pip Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2121
Cys Cys Glu NMe-Leu Cys Cys Asn Ile Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2122
Cys Cys Glu NMe-Leu Cys Cys Asn Ala Ala Cys Ala Gly Cys Trp


 


SEQ ID NO: 2123
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2124
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2125
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2126
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2127
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2128
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2129
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2130
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2131
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2132
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2133
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2134
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2135
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2136
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2137
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2138
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2139
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2140
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2141
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2142
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2143
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2144
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2145
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2146
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2147
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2148
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2149
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2150
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2151
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2152
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2153
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2154
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2155
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2156
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2157
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2158
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2159
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2160
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2161
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2162
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2163
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2164
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2165
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2166
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2167
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2168
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2169
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2170
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2171
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2172
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2173
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2174
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2175
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2176
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2177
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2178
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2179
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2180
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2181
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2182
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2183
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2184
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2185
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2186
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2187
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2188
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2189
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2190
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2191
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2192
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2193
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2194
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2195
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2196
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2197
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2198
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2199
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2200
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2201
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2202
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2203
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2204
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2205
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2206
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2207
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2208
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2209
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2210
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2211
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2212
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2213
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2214
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2215
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2216
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2217
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2218
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2219
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2220
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2221
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2222
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2223
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2224
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2225
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2226
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2227
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2228
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2229
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2230
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2231
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2232
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2233
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2234
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2235
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2236
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2237
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2238
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2239
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2240
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2241
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2242
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2243
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2244
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2245
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2246
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2247
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2248
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2249
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2250
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2251
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2252
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2253
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2254
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2255
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2256
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2257
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2258
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2259
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2260
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2261
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2262
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2263
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2264
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2265
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2266
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2267
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2268
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2269
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2270
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2271
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2272
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2273
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2274
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2275
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2276
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2277
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2278
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2279
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2280
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2281
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2282
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2283
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2284
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2285
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2286
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2287
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2288
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2289
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2290
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2291
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2292
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2293
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2294
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2295
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2296
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2297
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2298
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2299
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2300
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2301
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2302
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2303
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2304
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2305
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2306
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2307
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2308
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2309
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2310
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2311
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2312
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2313
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2314
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2315
Cys Cys Glu hLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2316
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2317
Cys Cys Glu norLeu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2318
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2319
Cys Cys Glu ChxAla Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2320
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2321
Cys Cys Glu ChxIle Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2322
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2323
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2324
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2325
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2326
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2327
Cys Cys Glu Dopa Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2328
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2329
Cys Cys Glu NMe-Leu Cys Cys Asn Pro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2330
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2331
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2332
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2333
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2334
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2335
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2336
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2337
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2338
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2339
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2340
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2341
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2342
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2343
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2344
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2345
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2346
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2347
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2348
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2349
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2350
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2351
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2352
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2353
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2354
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2355
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2356
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2357
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2358
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2359
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2360
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2361
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2362
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2363
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2364
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2365
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2366
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2367
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2368
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2369
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2370
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2371
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2372
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2373
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2374
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2375
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2376
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2377
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2378
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2379
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2380
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2381
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2382
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2383
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2384
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2385
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2386
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2387
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2388
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2389
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2390
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2391
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2392
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2393
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2394
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2395
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2396
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2397
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2398
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2399
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2400
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2401
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2402
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2403
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2404
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2405
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2406
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2407
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2408
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2409
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2410
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2411
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2412
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2413
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2414
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2415
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2416
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2417
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2418
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2419
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2420
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2421
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2422
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2423
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2424
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2425
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2426
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2427
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2428
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2429
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2430
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2431
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2432
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2433
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2434
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2435
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Thr D-Ala Cys Tyr


 


SEQ ID NO: 2436
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Ser D-Ala Cys Tyr


 


SEQ ID NO: 2437
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2438
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4MeO-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2439
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4NO2-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2440
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 5F-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2441
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4MeF3-Phe D-Ala Cys Tyr


 


SEQ ID NO: 2442
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Thr Gly Cys Ile


 


SEQ ID NO: 2443
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Ser Gly Cys Ile


 


SEQ ID NO: 2444
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Ile


 


SEQ ID NO: 2445
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Ile


 


SEQ ID NO: 2446
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Ile


 


SEQ ID NO: 2447
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Ile


 


SEQ ID NO: 2448
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Ile


 


SEQ ID NO: 2449
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Thr Gly Cys Trp


 


SEQ ID NO: 2450
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Ser Gly Cys Trp


 


SEQ ID NO: 2451
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4F-Phe Gly Cys Trp


 


SEQ ID NO: 2452
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4MeO-Phe Gly Cys Trp


 


SEQ ID NO: 2453
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4NO2-Phe Gly Cys Trp


 


SEQ ID NO: 2454
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 5F-Phe Gly Cys Trp


 


SEQ ID NO: 2455
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys 4MeF3-Phe Gly Cys Trp


 


SEQ ID NO: 2456
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2457
Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2458
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2459
Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2460
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2461
Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2462
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2463
Cys Cys Glu Leu Cys Cys Asn Pip Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2464
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2465
Cys Cys Glu Leu Cys Cys Asn Ile Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2466
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Ile


 


SEQ ID NO: 2467
Cys Cys Glu Leu Cys Cys Asn Ala Ala Cys Ala D-Ala Cys Trp


 


SEQ ID NO: 2468
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Ile


 


SEQ ID NO: 2469
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr D-Ala Cys Trp


 


SEQ ID NO: 2470
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Ile


 


SEQ ID NO: 2471
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ser D-Ala Cys Trp


 


SEQ ID NO: 2472
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Ile


 


SEQ ID NO: 2473
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4F-Phe D-Ala Cys Trp


 


SEQ ID NO: 2474
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Ile


 


SEQ ID NO: 2475
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeO-Phe D-Ala Cys Trp


 


SEQ ID NO: 2476
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Ile


 


SEQ ID NO: 2477
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4NO2-Phe D-Ala Cys Trp


 


SEQ ID NO: 2478
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Ile


 


SEQ ID NO: 2479
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 5F-Phe D-Ala Cys Trp


 


SEQ ID NO: 2480
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Ile


 


SEQ ID NO: 2481
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys 4MeF3-Phe D-Ala Cys Trp









Scheme 2 shows the peptide sequences of the invention and the location of residues that may be modified, and exemplary modifications that may be made at each residue, to result in a therapeutic peptide.










SCHEME 2











(N-term. tail)
CORE:
(C-term.)









position-no.:



























1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
18
17
18
19









sequence:



























Asn
Thr
Phe
Tyr
Cys
Cys
Glu
Leu
Cys
Cys
Asn
Pro
Ala
Cys
Ala
Gly
Cys
Tyr
Tyr





substi-
Ser
Ser
Tyr
Phe
Pen
Pen
Ser
Thr
Pen
Pen

Dhp

Pen
Thr
D-Ala
Pen




tutions:
Thr
Asn

Trp
Mpr

hSer
hLeu



Thz


Ser


Phe
Phe









Csa
norLeu



HyPro


4F-Phe


Ile
Ile










ChxAla



Pip


4Me 


Trp
Trp

















O-Phe














ChxIle



Ile


4NO2-





















Phe














Phe



Ala


5F-Phe














Tyr






4MeF 





















3-Phe














Dopa



PRa

















NMe-



PRb


PHa














Leu

























PRc


PHb














THa



PRd


PHc














THb



PRe


PHd














THc



PRf


PHq














THd



PRg


PHf














THe



PRh


PHg














THf



PRi


PHh














THg



PRj


PHi














THh



PRk


PHj














THi



PRl


PHk














THj



PRm


PHl














THk



PRn


PHm














THl



PRq


PHn


















PRp


PHo





















PHp
















TABLE 4





Abbreviations used in Scheme 2:
















Pen =
Penicillamine


hSer =
Homoserine, Hse


Csa =
Cysteic Acid


hLeu =
Homoleucine, Hle


norLeu =
Norleucine, Nle


ChxAla =
Cyclohexyl-Aalanine, Cha


ChxIle =
Cyclohexyl-Isoleucine, Chi


Dopa =
L-Dopa, L-dihydroxyphenylalanine


Dhp =
3,4,-dihydro-Proline, D-Pro 3,4-Dehydroproline


Thz =
Thiazolidine (4-thiazolidine-2-



carboxylic acid), Tzd


HyPro =
Hydroxy-Proline, Hyp, Hydroxyproline


Pip =
L-Pipecolic Acid


4F-Phe =
4-fluoro-Phenylalanine, Phe(4-F), 



4-fluorophenylalanine


4MeO-Phe =
4-methoxy-Phenylalanine, Phe(4-OMe), 



4-methoxyphenylalanine


4NO2-Phe =
4-nitro-Phenylalanine, Phe(4-NO2), 



4-Nitrophenylalanine


5F-Phe =
Pentafluoro-Phenylalanine, Phe(3-F), 



3-fluorophenylalanine


4MeF3-Phe =
Phe(4-MeF3), 4-trifluoromethylphenylalanine


NMe-Leu =
N-methyl-leucine, MeLeu, N-Methylleucine


D-Ala =
D-Alanine


Mpr =
3-mercaptoproprionic acid


▭ =
none (or deletion)





natural



amino acids
(L-amino acids unless otherwise stated)





Ala =
Alanine


Arg =
Arginine


Asn =
Asparagine


Asp =
Aspartic acid


Cys =
Cysteine


Glu =
Glutamic acid


Gln =
Glutamine


Gly =
Glycine


His =
Histidine


Ile =
Isoleucine


Leu =
Leucine


Lys =
Lysine


Met =
Methionine


Phe =
Phenylalanine


Pro =
Proline


Ser =
Serine


Thr =
Threonine


Try =
Tryptophan


Tyr =
Tyrosine


Val =
Valine


THa =
(S)-2-amino-3-hydroxypropanoic acid


THb =
(R)-2-amino-3-(methylsulfonyl)propanoic acid


THc =
(S)-2-amino-3-(2-hydroxyphenyl)propanoic acid


THd =
(S)-2-aminopent-4-enoic acid


THe =
(S)-2-amino-2-((R)-oxiran-2-yl)acetic acid


THf =
(S)-2-amino-2-(furan-2-yl)acetic acid


THg =
(S)-2-amino-2-((S)-morpholin-2-yl)acetic acid


THh =
(S)-2-amino-3-(dimethylamino)propanoic acid


THi =
(2R,3R)-2-amino-3-hydroxybutanoic acid


THj =
(R)-2-amino-2-(thiophen-2-yl)acetic acid


THk =
(S)-2-amino-3-morpholinopropanoic acid


THl =
(S)-2-amino-2-(pyridin-2-yl)acetic acid


PRa =
(S)-2,5-dihydro-1H-pyrrole-2-carboxylic acid


PRb =
(S)-piperidine-2-carboxylic acid


PRc =
(S)-azetidine-2-carboxylic acid


PRd =
(S)-azepane-2-carboxylic acid


PRe =
2-(methylamino)acetic acid


PRf =
(S)-2-aminopropanoic acid


PRg =
2-am ino-2-methylpropanoic acid


PRh =
2-am ino-2,2-difluoroacetic acid


PRi =
(1S,9bS)-2,3,4,4a,5,9b-hexahydro-1H-pyrido



[4,3-b]indole-1-carboxylic acid


PRj =
(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic 



acid


PRk =
(S)-1,2-dihydroazete-2-carboxylic acid


PRl =
(S)-2,5-dihydro-1H-pyrrole-2-carboxylic acid


PRm =
(2S)-4-hydroxypyrrolidine-2-carboxylic acid


PRn =
(S)-5-thioxopyrrolidine-2-carboxylic acid


PRq =
(S)-thiazolidine-2-carboxylic acid


PRp =
(R)-5,5-dimethylthiazolidine-4-carboxylic acid


PHa =
(S)-2-amino-3-phenylpropanoic acid


PHb =
(S)-2-amino-3-(pyridin-4-yl)propanoic acid


PHc =
(S)-2-amino-3-(pyridin-3-yl)propanoic acid


PHd =
(S)-2-amino-3-(pyridin-2-yl)propanoic acid


PHq =
(S)-2-amino-3-(thiophen-2-yl)propanoic acid


PHf =
(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic 



acid


PHg =
(S)-2-aminopent-4-ynoic acid


PHh =
(S)-2,4-diamino-4-iminobutanoic acid


PHi =
(S)-2-amino-4-methylpent-4-enoic acid


PHj =
(S)-2-amino-4-methylpentanoic acid


PHk =
(S)-2-amino-3-cyclopropylpropan-1-ol


PHl =
(S)-2-amino-2-phenylacetic acid


PHm =
(S)-2-amino-3-cyclohexylpropanoic acid


PHn =
(S)-2-amino-3-(piperidin-4-yl)propanoic acid


PHo =
(S)-2-aminohexanoic acid


PHp =
(S)-2-aminopent-4-enoic acid









Additional Non-Natural Amino Acid Modifications

Figures and tables below contain additional non-natural amino acids that are useful substituents in STa peptide analogues of the present invention.
FIG. 1 illustrates non-natural analogues of threonine that are useful substituents in STa peptide analogues of the present invention, as further identified in Table 5.







TABLE 5





Threonine analogues


Threonine analogue abbreviations in FIG 1.

















 1
THa
(S)-2-amino-3-hydroxypropanoic acid


 2
THb
(R)-2-amino-3-(methylsulfonyl)propanoic acid


 3
THc
(S)-2-amino-3-(2-hydroxyphenyl)propanoic acid


 4
THd
(S)-2-aminopent-4-enoic acid


 5
THe
(S)-2-amino-2-((R)-oxiran-2-yl)acetic acid


 6
THf
(S)-2-amino-2-(furan-2-yl)acetic acid


 7
THg
(S)-2-amino-2-((S)-morpholin-2-yl)acetic acid


 8
THh
(S)-2-amino-3-(dimethylamino)propanoic acid


 9
THi
(2R,3R)-2-amino-3-hydroxybutanoic acid


10
THj
(R)-2-amino-2-(thiophen-2-yl)acetic acid


11
THk
(S)-2-amino-3-morpholinopropanoic acid


12
THl
(S)-2-amino-2-(pyridin-2-yl)acetic acid









FIG. 2 illustrates non-natural analogues of proline that are useful substituents in STa peptide analogues of the present invention, as further identified in Table 6.







TABLE 6





Proline analogues


Proline analogue abbreviations in FIG 2.

















 1
PRa
(S)-2,5-dihydro-1H-pyrrole-2-carboxylic acid


 2
PRb
(S)-piperidine-2-carboxylic acid


 3
PRc
(S)-azetidine-2-carboxylic acid


 4
PRd
(S)-azepane-2-carboxylic acid


 5
PRe
2-(methylamino)acetic acid


 6
PRf
(S)-2-aminopropanoic acid


 7
PRg
2-amino-2-methylpropanoic acid


 8
PRh
2-amino-2,2-difluoroacetic acid


 9
PRi
(1S,9bS)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]




indole-1-carboxylic acid


10
PRj
(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid


11
PRk
(S)-1,2-dihydroazete-2-carboxylic acid


12
PRl
(S)-2,5-dihydro-1H-pyrrole-2-carboxylic acid


13
PRm
(2S)-4-hydroxypyrrolidine-2-carboxylic acid


14
PRn
(S)-5-thioxopyrrolidine-2-carboxylic acid


15
PRq
(S)-thiazolidine-2-carboxylic acid


16
PRp
(R)-5,5-dimethylthiazolidine-4-carboxylic acid









FIG. 3 illustrates non-natural analogues of phenylalanine that are useful substituents in STa peptide analogues of the present invention, as further identified in Table 7.







TABLE 7





Phenylalanine analogues


Phenylalanine analogue abbreviations in FIG 3.

















 1
PHa
(S)-2-amino-3-phenylpropanoic acid


 2
PHb
(S)-2-amino-3-(pyridin-4-yl)propanoic acid


 3
PHc
(S)-2-amino-3-(pyridin-3-yl)propanoic acid


 4
PHd
(S)-2-amino-3-(pyridin-2-yl)propanoic acid


 5
PHq
(S)-2-amino-3-(thiophen-2-yl)propanoic acid


 6
PHf
(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid


 7
PHg
(S)-2-aminopent-4-ynoic acid


 8
PHh
(S)-2,4-diamino-4-iminobutanoic acid


 9
PHi
(S)-2-amino-4-methylpent-4-enoic acid


10
PHj
(S)-2-amino-4-methylpentanoic acid


11
PHk
(S)-2-amino-3-cyclopropylpropan-1-ol


12
PHl
(S)-2-amino-2-phenylacetic acid


13
PHm
(S)-2-amino-3-cyclohexylpropanoic acid


14
PHn
(S)-2-amino-3-(piperidin-4-yl)propanoic acid


15
PHo
(S)-2-aminohexanoic acid


16
PHp
(S)-2-aminopent-4-enoic acid









Additional embodiments include but are not limited to those shown in the following Table 8A [and Table 8B?] showing single and double substitutions that may be used in the practice of the invention. One skilled in the art will appreciate that triple mutations comprising the various substitutions shown in the above schemes are also within the scope of the present invention. The embodiments shown in the tables are shown without the first four amino acids on the N-terminal and the C-terminal residue (residues 1-4 and 19 were left off). The amino acids shown in scheme 2 may be optionally included at these positions on the sequences shown in the tables.







TABLE 8A





Single mutations from Scheme 2, excluding sequences


included in table 3A:
















SEQ ID NO: 2500
Cys Cys Glu THa Cys Cys Asn Pro



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2501
Cys Cys Glu THb Cys Cys Asn Pro 



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2502
Cys Cys Glu THc Cys Cys Asn Pro



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2503
Cys Cys Glu THd Cys Cys Asn Pro



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2504
Cys Cys Glu TRe Cys Cys Asn Pro



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2505
Cys Cys Glu THE Cys Cys Asn Pro



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2506
Cys Cys Glu THg Cys Cys Asn Pro



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2507
Cys Cys Glu THh Cys Cys Asn Pro



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2508
Cys Cys Glu THi Cys Cys Asn Pro



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2509
Cys Cys Glu THj Cys Cys Asn Pro



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2510
Cys Cys Glu THk Cys Cys Asn Pro



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2511
Cys Cys Glu THI Cys Cys Asn Pro



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2512
Cys Cys Glu Leu Cys Cys Asn PRa



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2513
Cys Cys Glu Leu Cys Cys Asn PRb



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2514
Cys Cys Glu Leu Cys Cys Asn PRc



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2515
Cys Cys Glu Leu Cys Cys Asn PRd



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2516
Cys Cys Glu Leu Cys Cys Asn PRe



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2517
Cys Cys Glu Leu Cys Cys Asn PRf



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2518
Cys Cys Glu Leu Cys Cys Asn PRg



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2519
Cys Cys Glu Leu Cys Cys Asn PRh



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2520
Cys Cys Glu Leu Cys Cys Asn PRi



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2521
Cys Cys Glu Leu Cys Cys Asn PRj



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2522
Cys Cys Glu Leu Cys Cys Asn PRk



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2523
Cys Cys Glu Leu Cys Cys Asn PRI



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2524
Cys Cys Glu Leu Cys Cys Asn PRm



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2525
Cys Cys Glu Leu Cys Cys Asn PRn



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2526
Cys Cys Glu Leu Cys Cys Asn PRq



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2527
Cys Cys Glu Leu Cys Cys Asn PRp



Ala Cys Ala Gly Cys Tyr


 


SEQ ID NO: 2528
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHa Gly Cys Tyr


 


SEQ ID NO: 2529
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHb Gly Cys Tyr


 


SEQ ID NO: 2530
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHc Gly Cys Tyr


 


SEQ ID NO: 2531
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHd Gly Cys Tyr


 


SEQ ID NO: 2532
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHq Gly Cys Tyr


 


SEQ ID NO: 2533
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHf Gly Cys Tyr


 


SEQ ID NO: 2534
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHg Gly Cys Tyr


 


SEQ ID NO: 2535
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHh Gly Cys Tyr


 


SEQ ID NO: 2536
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHi Gly Cys Tyr


 


SEQ ID NO: 2537
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHj Gly Cys Tyr


 


SEQ ID NO: 2538
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHk Gly Cys Tyr


 


SEQ ID NO: 2539
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHI Gly Cys Tyr


 


SEQ ID NO: 2540
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHm Gly Cys Tyr


 


SEQ ID NO: 2541
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHn Gly Cys Tyr


 


SEQ ID NO: 2542
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHo Gly Cys Tyr


 


SEQ ID NO: 2543
Cys Cys Glu Leu Cys Cys Asn Pro



Ala Cys PHp Gly Cys Tyr









Modifications of the Peptides

In addition to the above specified peptides, one or more amino acids of the GCC peptides can be replaced by other amino acid that are not among the naturally occurring. For example, an aromatic amino acid can be replaced by 3,4-dihydroxy-L-phenylalanine, 3-iodo-L-tyrosine, triiodothyronine, L-thyroxine, phenylglycine or nor-tyrosine. Phenylglycine, nor-tyrosine, phenylalanine, tyrosine and other amino acids can be substituted by, e.g., a halogen, —CH3, —OH, —CH2NH3, —C(O)H, —CH2CH3, —CN, —CH2CH2CH3, —SH, or another group. Any amino acid can be substituted by the D-form of the amino acid. Alanine can be substituted with alpha-substituted or N-methylated amino acid such as alpha-amino isobutyric acid, LI D-alpha-ethylalanine, LID-methylvaline, or LID-alpha-methylleucine. Glutamine can be substituted with gamma-Hydroxy-Glu or gamma-Carboxy-Glu. Glycine can be substituted with alpha-amino isobutyric acid or LID-alpha-ethylalanine. Proline can be substituted with homoproline (L-pipecolic acid), hydroxy-Proline, 3,4-Dehydro-Proline, 4-fluoroproline or alpha-methyl-Proline. Tyrosine (Tyr) can be substituted with an alpha substituted amino acid such as L-alpha-methylphenylalanine or by other analogues such as A-MethylTrp, tBu-Gly, 3-Amino-Tyr, 5-Methyl-Trp, Amino-Phe, beta-(1-Cyclopentenyl)Ala, beta-(2-Pyridyl)-Ala, beta-(2-Thiazolyl)-Ala, beta-(2-thienyl)-Ala, beta-(3-benzothienyl)-Ala, beta-(3-Pyridyl)-Ala, beta-(Triazole-1-yl)Ala, beta-Cyclohexyl-Ala, beta-Cyclopentyl-Ala, beta-Cyclopropyl-Ala, betaQuinolyl-Ala, Cyclohexyl-Gly, and Fluoro-Phe.
Other examples include amino acids substituted with an alkyl, aryl, acyl, azido, borate, boronate, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynl, ether, ester, sulfonyl, seleno, thiol, thioacid, phospho, phosphono, phosphine, enone, imine, aldehyde or hydroxylamine. Other examples are amino acid with a radioactive amino acid, a spin-labeled amino acid, an amino acid with a photo-activatable cross-linker, 3-methyl-phenylalanine, 4-propyl-L-tyrosine, a disubstituted amino acid, a keto containing amino acid, a metal binding amino acid, p-iodo-phenylalanine, amino acids comprising polyethylene glycol or polyether, amino-isobutyric acid, an amino thio amino acid, isopropyl-L-phenylalanine, L-Dopa, nitro-arginine, norleucine, O-methyl-L-tyrosine, phosphonoserine, 3-nitro-tyrosine, 4-fluorophenylglycine, a biotin or biotin-analogue containing amino acid, a cyclic amino acid other than proline, a fluorinated phenylalanine, a glycosylated amino acid, a heavy atom substituted amino acid including an amino acid containing deuterium, a carbohydrate modified amino acid, p-(propargyloxy)-phenylalanine, a p-acetyl-L-phenylalanine, a p-acyl-L-phenylalanine, a redox-active amino acid, acetamidomethyl protected amino acids, aminobutyric acid, aminohexanoic acid, an amino acid containing a toxic group; a sugar substituted amino acid, Carbobenzoxyl, citrulline, cyclohexylalanine, D-3-(2-naphthyl)alanine, d-cyclohexylalanine, dimethyl-Lysine, E-Acetyl-Lysine, hydroxyproline, isopropyl-L-phenylalanine, L-3-(2-naphthyl)alanine, L-3-(2-naphthyl)alanine, L-phosphoserine, mercaptopropionic acid, methyl-lysine, nitrophenylalanine, nitro-tyrosine, norvaline, octahydroindole carboxylate, O-methyl-L-tyrosine, O-allyl ornithine, p-amino-L-phenylalanine, p-azido-L-phenylalanine, p-benzoyl-L-phenylalanine, p-bromophenylalanine, pegylated amino acids, penicillamine, isopropyl-phosphonotyrosine, pyro-glutamic acid, tetrahydroisoquinoline, tritium containing amino acids, or a fluorescent amino acid.
Further examples of unnatural amino acids and amino acid analogs can be found in (Schultz et al., 2002—US. 20030082575; Alfonta et al., 2010—U.S. Pat. No. 7,811,801; Cho et al., 2006—US20060019347; Shailubhai & Gary, 2009—US20090048175) and the references therein.
The GCC peptides can also be cyclic peptides. Cyclic peptide can be made through methods known in the art. For example, macrocyclization can be accomplished by forming an amide bond between the peptide N- and C-termini, or between a side chain and the N- or C-terminus, or between two amino acid side chains such as cysteine. The GCC peptides can also be bicyclic.
The disulphide bonds in the GCC peptides can also be modified. In some GCC peptides one or more members of one, two or all pairs of the cysteine residues which normally form a disulfide bond can be replaced by alternate residues, such as homocysteine, penicillamine, 3-mercaptoproline, dimethylcysteine or diaminopropionic acid to form alternative internal bridges at the positions of the normal disulfide bonds. One or more of the disulfide bonds can be replaced by alternative covalent cross-links, such as an amide linkage, an amine linkage, an alkenyl linkage, an alkyl linkage, a carbamoyl linkage, an ester linkage, a thioester linkage, a lactam linkage, a urea linkage, a thiourea linkage, a phosphonate ester linkage, an ether linkage, a thioether linkage, or a thioamide linkage.
The GCC peptides can have one or more of the polypeptide bonds replaced by an alternative bond. Such bonds may increase the peptide's activity or increase its stability by reducing cleavage by reductases, proteases or carboxy peptidases. Examples of bonds that can replace conventional polypeptide bonds include a reduced amide bond, an ethylene bond, a fluoro substituted trans-olefine bond, a fluoro-ketomethylene bond, a ketomethylene bond, a retro-inverso bond (a C(O)—NH instead of NH—C(O)), an oxomethylene bond, a thiomethylene bond, a thioamide bond, and a trans-olefine bond.
The GCC peptides can be modified by one or more modifications or one or more types of modification. Modifications may occur at the amino terminus, at the carboxy terminus, internally or a combination of any these. Non-limiting examples of are modifications by acetylation, amidation, 7-Amino-4-methyl-coumarin, amide cyclisation, biotinylation, cinnamoylation, cyclisation, disulfide bridges cyclisation, Cys3, Cys5, dabcyl, dabsyl, dansyl, farnesylation, FMOC, formylation, myristoylation, palmitoylation, phosphorylation, stearoylation, succinylation, sulfurylation, 2,4-dinitrophenyl, dinitrophenyl-lysine, flourescein, 7-Nitrobenz-2-oxa-1,3-Diazole, p-nitro-anilide, rhodamine B, 5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid, texas red, and tetramethylrhodamine.
The GCC peptides can also be conjugated. Non-limiting examples of conjugation include polyethylene glycol (PEG), Bovine Serum Albumine, Human Albumine, alkyl groups, C1 to C40 straight or branched alkyl groups, fatty acid radicals, Keyhole Limpet Hemocyanin, and combinations of any of the before mentioned conjugations (Ekwuribe et al., 2001—U.S. Pat. No. 6,309,633; Soltero & Ekwuribe 2001; Payne & Manning, 2009; Currie & Sterling 2010-US2006019347).
The GCC peptides can also be modified in different ways, as long as they retain most of the GCC receptor agonist potency or apoptosis inducing potency of the naturally occurring peptides, or more. The GCC peptides can also include versions which are modified or hybrid forms, in which some amino acids have been changed, replaced or deleted. This includes modifications such as glycosylation.
The GCC peptides include peptides where amino acid substitutions have been made at one or more non-essential amino acids. These are substitutions where the amino acids have been replaced with an amino acid that has a similar side chain. Groups of such amino acids include amino acids with acidic side chains (aspartic acid, glutamic acid), aromatic side chains (tyrosine, phenylalanine, tryptophan, histidine), basic side chains (lysine, arginine, histidine), branched side chains (threonine, valine, isoleucine), nonpolar side chains (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan) and uncharged polar side chains (glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine). In such substitutions, the non-essential amino acid is replaced with another amino acid from the same group, or randomly substituted along the GCC peptide.
Preparation of the Peptides
GCC peptides can be produced by various methods. For example, they can be prepared using recombinant cloning techniques, or synthesized de novo by chemical protocols, or by site-directed mutagenesis. Chemical synthesis may generally be performed using standard solution phase or solid phase peptide synthesis techniques, in which a peptide linkage occurs through the direct condensation of the amino group of one amino acid with the carboxy group of the other amino acid and the elimination of a water molecule. Such peptide bond synthesis usually requires suppression of reactive groups of both amino acids (US 2010/0093635 Al; Gongora-Benitez et al., 2010).
In the case of solution phase synthesis, a wide variety of coupling methods and protecting groups may be used (See, Gross and Meienhofer, eds., “The Peptides: Analysis, Synthesis, Biology,” Vol. 1-4 (Academic Press, 1979); Bodansky and Bodansky, “The Practice of Peptide Synthesis,” 2d ed. (Springer Verlag, 1994)).
In the case of solid phase peptide synthesis, an insoluble polymer is used for support during organic synthesis, permitting the use of simple washing and filtration steps. Solid-phase peptide synthesis can, for example, be performed according to the method of Merrifield et al., J. Am. Chem. Soc., 1963, 85:2149 involving assembling a linear peptide chain on a resin support using protected amino acids. Solid phase synthesis typically utilizes either the Boc or Fmoc strategy, which are well known in the art. Here, de-protection and coupling reactions must go to completion and the side-chain blocking groups must be stable throughout the synthesis. Typically, solid phase synthesis is more suitable when peptides are made on a small scale. Acetylation of the N-terminal can be achieved by reacting the last peptide with acetic anhydride before cleavage from the resin. C-amidation is carried out using an appropriate resin such as methylbenzhydrylamine resin using the Boc technology.
Mature peptides and variants thereof can also be synthesized on Cyc(4-CH2 Bxl)—OCH2-4-(oxymethyl)-phenylacetamidomethyl resin using a double coupling program. Protecting groups must be used appropriately to create the correct disulfide bond pattern. The resulting peptide is then purified by reverse-phase chromatography. Peptides can also be synthesized by many other methods including solid phase synthesis using traditional FMOC protection (i.e., coupling with DCC-HOBt and de-protection with piperidine in DMF). Cys thiol groups can be trityl protected. Treatment with TFA can be used for final de-protection of the peptide and release of the peptide from the solid-state resin. In many cases air oxidation is sufficient to achieve proper disulfide bond formation.
Alternatively, immature or mature forms of GCC peptides—consisting entirely of standard amino acids, or of standard amino acids that are easily derivatized—may be produced by recombinant cloning techniques in bacterial, baculovirus, yeast, fungal or mammalian cell expression systems.
Formulation of the Peptides
GCC peptides can be administered alone or in combination with other agents such as inhibitors of cGMP dependent phosphodiesterase, such as, for example, motapizone suldinac sulfone, zaprinast, vardenafil or sildenafil; chemotherapeutic agents; or anti-inflammatory drugs like steroids or non-steroidal anti-inflammatory drugs such as aspirin, antiviral agents, or anti-cancer agents. Combination treatment is achieved by administering two or more agents formulated and administered separately or in a single formulation, or formulated together and administered in conjunction with a formulation containing a third agent. Combination therapy can be applied simultaneously or at different times. For example, two or more agents can be administered within minutes of each other or within 1, 2, 3, 4, 6, 9, 12, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. Even shorter or longer intervals are possible.
The GCC peptides described herein may be combined with phosphodiesterase inhibitors, e.g., motapizone, sulindae sulfone, zaprinast, sildenafil, vardenafil or tadalafil to further or with azathioprine and/or other immunomodulating agents. The immunomodulating agents may include small molecule drugs and biologics such as Remicade, Humira, Cimzia etc.
Other agents that may be combined with GCC peptides described herein are cisdapride, Cimetropium, dolasetron, trimebutine maleate, diciclomine, cholestyramine, darifenacin, Calcium polycarbophil, ondansetron, tegaserod, hysvyamine sulfate, pinaverium bromide, mebeverine, granisetron, propanthiline bromide, alosetron hydrochloride, rifaximin, bumetanide. GCC peptides may also be used in combination with agents to treat gastrointestinal cancers, Crohn's Disease, Ulcerative Colitis, Constipation, Irritable Bowel Syndrome, postoperative Ileus, including phosphodiesterase inhibitors, analgesic agents, anti-viral agents, anti-cancer agents, anti-inflammatory agents, and anti-obesity agents. Agent combination therapy may also be administered via different routes or locations, e.g. one orally, another intravenously or locally.
Approximated dosages for some of the combination therapy agents described herein are found in the “BNF Recommended Dose” column of tables on pages 11-17 of WOO 11 76632 and can also be found in other standard formularies and other drug prescribing directories. For some drugs, the customary prescribed dose will vary from country to country.
GCC peptides, alone or in combination, can be added to any common pharmaceutical carrier or medium and can thus be combined with materials that do not produce an adverse, allergic or otherwise unwanted reaction in a patient. Such carriers or mediums include solvents, coatings, dispersants, absorption promoting agents, controlled release agents, and one or more inert excipients (which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and similar), etc. If desired, tablet or capsule dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques. It is to be understood that a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration are parenteral, e.g., intravenous, intradermal, subcutaneous, oral, inhalation, transdermal, topical, transmucosal, and rectal. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include for example: a sterile diluent such as water for injection, saline solution, oils, glycerine, polyethylene glycols, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride, sucrose or dextrose. The pH can be adjusted with acids or bases.
Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, or phosphate buffered saline (PBS). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and the similar), and mixtures thereof. The proper fluidity of the dispersion can be reached, for example, by the use of a coating such as lecithin, by the appropriate particle size in the case of dispersion and by the use of surfactants. Prevention if growth of microrganisms can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, ascorbic acid, thimerosal, and the like. In some cases, inclusion of isotonic agents will be required, for example, sugars, polyalcohols such as manitol, sorbitol or sodium chloride. Delayed or prolonged absorption of the agent or combination of agents can be achieved by including an compositions which delays absorption, such as aluminum monostearate and gelatin.
Sterile solutions for injection can be prepared by mixing the active compound with an appropriate solvent with one or a combination of ingredients, as required, followed by filtered sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the required other ingredient. For sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a sterile solution thereof.
Oral route compositions typically include an inert diluent or carrier like mannitol, fructooligosaccharides, polyethylene glycol along with other excipients, which can be enclosed in capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, capsules or troches. Oral route compositions can also be prepared using a fluid carrier wherein the compound in the fluid carrier is applied orally and expectorated or swallowed. Pharmaceutically compatible binding agents and materials can be included in the composition. It can contain any of the following or similar components: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, a disintegrating agents such as alginic acid or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; a wetening agents such as sucrose or saccharin; flavoring agents such as peppermint or orange flavoring.
For inhalation, the agents can be delivered in the form of an aerosol spray from container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or from a nebulizer.
Systemic administration can for example be by transmucosal or transdermal means. For transmucosal or transdermal administration, appropriate penetrant enhancers are used in the formulation. These are generally known in the art, and include, for example, detergents and bile salts. Transmucosal administration can be achieved through use of nasal sprays or suppositories. For transdermal administration, the active compounds may be formulated into ointments, salves, gels, or creams as generally known in the art. The agents may also be prepared in the form of suppositories with conventional suppository bases such as cocoa butter and other glycerides, or as retention enemas for rectal delivery.
In another embodiment, the active agents are combined with carriers that will prevent the compound from being rapid eliminated from the body. Such delayed or controlled release formulation may include implants, microencapsulated delivery systems, biodegradable polymers (such as polyanhydrides, polyglycolic acid, collagen and polyorthoesters). Methods for preparation of these compositions are well known to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers, according to methods known to those skilled in the art (see, for example U.S. Pat. No. 4,522,811).
An oral or parenteral compositions in dosage unit form can be formulated and packaged for ease of administration and uniformity of dosage. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
Formulations of the present invention may also include other therapeutic ingredients and non-active ingredients, such as anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, glidants, anti-adherents, antistatic agents, surfactants, anti-oxidants and the like. The formulation may also contain other additives as needed, including for example lactose, glucose, fructose, galactose, sucrose, maltose, mannitol, myoinositol, raffnose, maltitol, stachyose, lactitol, palatinite, starch, xylitol, and the like, and hydrates thereof, and amino acids, for example alanine, glycine, and polypeptides and proteins, for example albumen.
Many types of substances can be used as pharmaceutically acceptable excipients. Non-binding examples include binders, fillers, disintegrants, lubricants, antimicrobial agents, and coating agents such as: BINDERS: corn starch, potato starch, other starches, gelatin, natural and synthetic gums, xanthan, sodium alginate, alginates, guar gum, cellulose and cellulose derivatives, e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, polyvinyl pyrrolidones, e.g., povidone, crospovidone, copovidone, methyl cellulose, pre-gelatinized starch, microcrystalline cellulose, or mixtures thereof; FILLERS: talc, calcium carbonate, dibasic or tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, dextrates, mannitol, silicic acid, sorbitol, starch, dextrose, fructose, lactose anhydrate, lactose, aspartame, maltose, mannitol, microcrystalline cellulose & amp; guar gum, sucrose, or mixtures thereof; DISINTEGRANTS: agar, alginic acid, calcium carbonate, microcrystalline cellulose, polacrilin potassium, tapioca starch, pregelatinized starch, clays, gums; LUBRICANTS: calcium stearate, magnesium stearate, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium stearyl fumarate, talc, hydrogenated vegetable oil, zinc stearate, syloid silica gel or mixtures thereof; ANTI-CAKING AGENTS: calcium silicate, magnesium silicate, colloidal silicon dioxide, talc, or mixtures thereof; ANTIMICROBIAL AGENTS: benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, cresol, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenoxyethanol, phenylmercuric acetate, phenylmercuric nitrate, sodium dehydroacetate, sodium propionate, sorbic acid, thimersol, thymo, or mixtures thereof; COATING AGENTS: sodium carboxymethyl cellulose, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose phthalate, methylcellulose, polyethylene glycol, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, gellan gum, maltodextrin, methacrylates, microcrystalline cellulose, or mixtures thereof.
The formulation may also include other excipients including but not limited to L-histidine, Pluronic, Poloxamers (such as Lutrol and Poloxamer 188), ascorbic acid, glutathione, permeability enhancers (e.g. lipids, sodium cholate, salicylates, mixed bile salts, fatty acid micelles, chelators), protease inhibitors (e.g. trypsin inhibitors, organic acids), pH lowering agents and absorption enhancers (see for example U.S. Pat. No. 6,086,918 and U.S. Pat. No. 5,912,014), creams and lotions; materials for chewable tablets (like dextrose, fructose, maltodextrin, maltose, mannitol, guar gum, sorbitol crystalline); parenterals (like mannitol and povidone); plasticizers (like dibutyl sebacate, polyvinylacetate phthalate); powder lubricants (like glyceryl behenate); soft gelatin capsules; spheres for coating; spheronization agents (like microcrystalline cellulose); suspending/gelling agents (like gellan gum, mannitol, microcrystalline cellulose, povidone, sodium starch); sweeteners (like aspartame, aspartame and lactose, dextrose, fructose, maltodextrin, maltose, mannitol, sucrose); wet granulation agents (like calcium carbonate, lactose anhydrous, lactose monohydrate, maltodextrin, mannitol), caramel, carboxymethylcellulose sodium, flavoring agents, citric acid, confectioner's sugar, disodium edetate, FD&C Yellow No. 6 aluminum lake, FD&C Blue No. 1, FD&C blue no. 2 aluminum lake, glycerol palmitostearate, glyceryl monostearate, orange flavor, strawberry flavor, synthetic black iron oxide, synthetic red iron oxide and titanium dioxide.
Formulations for oral dosage may also be treated with coating systems to create a sustained release formulation, for example Opadry blue (OY-LS-20921) and Opadry white (YS-2-7063). Compounds either in their free form or as a salt can be combined with a polymers such as poly-(1)-lactic-glycolic-tartaric acid, polyglycolic acid and poly alkylene oxide (U.S. 20030068384). Such formulations can be used within implants that releases a the agent over a period of a few days, a few weeks or several months. Other examples of sustained release formulations and polymers are described in WO 97/40085, WO 03/075887, WO 93/24150, U.S. Pat. No. 5,612,052, WO 01101964A2, U.S. Pat. No. 5,922,356, WO 941155587, WO 02/074247A2, WO 98/25642, U.S. Pat. No. 5,968,895, U.S. Pat. No. 6,180,608, U.S. 20030171296. U.S. Pat. No. 5,192,741, U.S. Pat. No. 5,192,741, U.S. Pat. No. 4,668,506, U.S. 20020176841, U.S. Pat. No. 5,672,659, U.S. Pat. No. 5,893,985, U.S. Pat. No. 5,134,122, U.S. Pat. No. 4,713,244, and US20020019446. One or more sustained release implants can be placed in the stomach, the large intestine, the small intestine or both. Examples controlled release formulations are described in U.S. 20030138488A1, U.S. 20030216307 Al, U.S. Pat. No. 6,667,060, WO 01/49249, WO02/38129, EP 326151, U.S. Pat. No. 5,236,704, WO 02/30398, WO 98/13029; U.S. 20030064105 and WO 01149311. Example materials, which may be included are described in WO04041195. pH-sensitive coatings that achieve delivery in the colon includes those described in U.S. Pat. No. 4,910,021 and WO9001329 U.S. Pat. No. 4,910,021, WO9001329 and U.S. Pat. No. 5,175,003.
The GCC peptides described herein can be formulated in a pH triggered targeted control release systems such as described in WO04052339 or according to the methodology described in WO03105812, WO02072075, WO05063156, WO0243767, WO03007913, WO03086297, WO04064769, WO03035029, WO03035041,U.S. Pat. No. 5,007,790, U.S. Pat. No. 5,972,389, WO05027878, WO02072033, WO02072034, WO05030182, WO05048998, U.S. Pat. No. 5,108,758, U.S. Pat. No. 5,952,314, U.S. Pat. No. 5,840,860, U.S. Pat. No. 5,866,619, U.S. Pat. No. 6,368,629, U.S. Pat. No. 6,531,152, U.S. Pat. No. 6,234,464; U.S. Pat. No. 6,403,130, WO0174 175 and WO040 19872.
The GCC peptides described herein may be formulated using a gastrointestinal retention system technology such as GIRES (Merrion Pharmaceuticals). GIRES comprises a controlled-release dosage form inside an inflatable pouch, which is placed in a drug capsule for oral administration. Upon dissolution of the capsule, a gas-generating system inflates the pouch in the stomach where it is retained for 16-24 hours, all the time releasing agents.
GCC peptides can also be formulated using an osmotic device as those disclosed in U.S. Pat. No. 4,503,030, U.S. Pat. No. 5,609,590 and U.S. Pat. No. 5,358,502 and U.S. Pat. No. 4,503,030. The GCC peptide can also be formulated in an osmotic bursting device as described in U.S. Pat. Nos. 5,609,590 and 5,358,502.
Dosage of the Peptides
The dose range of administered agent for adult humans is generally from 0.005 mg to 10 g/day. A dosage unit (e.g. an oral dosage unit) can include from, for example, 1 to 30 ug, 1 to 40 ug, 1 to 50 ug, 1 to 100 ug, 1 to 200 ug, 1 to 300 ug, 1 to 400 ug, 1 to 500 ug, 1 to 600 ug, 1 to 700 ug, 1 to 800 ug, 1 to 900 ug, 1 to 1000 ug, 10 to 30 ug, 10 to 40 ug, 10 to 50 ug, 10 to 100 ug, 10 to 200 ug, 10 to 300 ug, 10 to 400 ug, 10 to 500 ug, 10 to 600 ug, 10 to 700 ug, 10 to 800 ug, 10 to 900 ug, 10 to 1000 ug, 100 to 200 ug, 100 to 300 ug, 100 to 400 ug, 100 to 500 ug; 100 to 600 ug, 100 to 700 ug, 100 to 800 ug, 100 to 900 ug, 100 to 1000 ug, 100 to 1250 ug, 100 to 1500 ug, 100 to 1750 ug, 100 to 2000 ug, 100 to 2250 ug, 100 to 2500 ug, 100 to 2750 ug, 100 to 3000 ug, 200 to 300 ug, 200 to 400 ug, 200 to 500 ug, 200 to 600 ug, 200 to 700 ug, 200 to 800 ug, 200 to 900 ug, 200 to 1000 ug, 200 to 1250 ug, 200 to 1500 ug, 200 to 1750 ug, 200 to 2000 ug, 200 to 2250 ug, 200 to 2500 ug, 200 to 2750 ug, 200 to 3000 ug, 300 to 400 ug, 300 to 500 ug, 300 to 600 ug, 300 to 700 ug, 300 to 800 ug, 300 to 900 ug, 300 to 1000 ug, 300 to 1250 ug, 300 to 1500 ug, 300 to 1750 ug, 300 to 2000 ug, 300 to 2250 ug, 300 to 2500 ug, 300 to 2750 ug, 300 to 3000 ug, 400 to 500 ug, 400 to 600 ug, 400 to 700 ug, 400 to 800 ug, 400 to 900 ug, 400 to 1000 ug, 400 to 1250 ug, 400 to 1500 ug, 400 to 1750 ug, 400 to 2000 ug, 400 to 2250 ug, 400 to 2500 ug, 400 to 2750 ug, 400 to 3000 ug, 500 to 600 ug, 500 to 700 ug, 500 to 800 ug, 500 to 900 ug, 500 to 1000 ug, 500 to 1250 ug, 500 to 1500 ug, 500 to 1750 ug, 500 to 2000 ug, 500 to 2250 ug, 500 to 2500 ug, 500 to 2750 ug, 500 to 3000 ug, 600 to 700 ug, 600 to 800 ug, 600 to 900 ug, 600 to 1000 ug, 600 to 1250 ug, 600 to 1500 ug, 600 to 1750 ug, 600 to 2000 ug, 600 to 2250 ug, 600 to 2500 ug, 600 to 2750 ug, 600 to 3000 ug, 700 to 800 ug, 700 to 900 ug, 700 to 1000 ug, 700 to 1250 ug, 700 to 1500 ug, 700 to 1750 ug, 700 to 2000 ug, 700 to 2250 ug, 700 to 2500 ug, 700 to 2750 ug, 700 to 3000 ug, 800 to 900 ug, 800 to 1000 ug, 800 to 1250 ug, 800 to 1500 ug, 800 to 1750 ug, 800 to 2000 ug, 800 to 2250 ug, 800 to 2500 ug, 800 to 2750 ug, 800 to 3000 ug, 900 to 1000 ug, 900 to 1250 ug, 900 to 1500 ug, 900 to 1750 ug, 900 to 2000 ug, 900 to 2250 ug, 900 to 2500 ug, 900 to 2750 ug, 900 to 3000 ug, 1000 to 1250 ug, 1000 to 1500 ug, 1000 to 1750 ug, 1000 to 2000 ug, 1000 to 2250 ug, 1000 to 2500 ug, 1000 to 2750 ug, 1000 to 3000 ug, 2 to 500 ug, 50 to 500 ug, 3 to 100 ug, 5 to 20 ug, 5 to 1100 ug, 10 ug, 20 ug, 30 ug, 40 ug, 50 ug, 60 ug, 70 ug, 75 ug, 80 ug, 90 ug, 100 ug, 150 ug, 200 ug, 250 ug, 300 ug, 350 ug, 400 ug, 450 ug, 500 ug, 550 ug, 600 ug, 650 ug, 700 ug, 750 ug, 800 ug, 850 ug, 900 ug, 950 ug, 1000 ug, 1050 ug, 1100 ug, 1150 ug, 1200 ug, 1250 ug, 1300 ug, 1350 ug, 1400 ug, 1450 ug, 1500 ug, 1550 ug, 1600 ug, 1650 ug, 1700 ug, 1750 ug, 1800 ug, 1850 ug, 1900 ug, 1950 ug, 2000 ug, 2050 ug, 2100 ug, 2150 ug, 2200 ug, 2250 ug, 2300 ug, 2350 ug, 2400 ug, 2450 ug, 2500 ug, 2550 ug, 2600 ug, 2650 ug, 2700 ug, 2750 ug, 2800 ug, 2850 ug, 2900 ug, 2950 ug, 3000 ug, 3250 ug, 3500 ug, 3750 ug, 4000 ug, 4250 ug, 4500 ug, 4750 ug, 5000 ug of a peptide described herein.
Ileal and Colonic Site of Action in Accordance with the Present Invention
According to the present invention, it has been surprisingly discovered that ileal and colonic release formulations of the invention have therapeutic potential for treating a number of clinical conditions including, for example, the treatment of constipation, irritable bowel syndrome, a wide variety of inflammatory conditions, and as anti-metastatic agents in the treatment of cancer. In particular, the invention has discovered therapeutic advantages for releasing a secretagouge such as a GCCR agonist peptide in the distal jejunum, ileum, cecum and proximal colon for the treatment of Chronic Idiopathic Constipation and Irritable Bowel Syndrome.
The present invention recognizes several reasons why the distal jejunum, ileum, cecum and proximal colon is the preferred target for an effective GCCR agonist and for any secretagouge intended for the treatment of CIC and IBS-c and IBS-m. These reasons include, for instance the distribution of Guanylyl Cyclase C receptor in the intestine: In addition to the duodenum, the ileum, cecum, and colon also express significant GCCR activity and function. Moreover, STa peptides are much more stable in the ileum than in the duodenum: Half life in duodenum about 3 minutes but about 30 minutes in the ileum (Kessler et al, 2009; Kessler et al, 2008).
In addition, delivery of a GCCR agonist to the distal jejunum, ileum and proximal colon provides much better control of stool hydration: Most fluid that enters the duodenum is absorbed in the jejunum and ileum (Feldman et al., 2006). An agonist acting in the duodenum must contribute large amounts of fluid, possibly as much as up to 3 liters, to overcome this. The absorption of this large fluid flow through the intestine is variable. This causes large swings in stool hydration and causes occasional diarrhea. Avoiding this diarrhea limits dose range and efficacy. Thus, slow release delivery to the distal jejunum, ileum, cecum and proximal colon can provide several hours of low level fluid secretion. This creates a smaller and slower fluid flow closer to the colon. Less fluid contribution is required, as the fluid will not be re-absorbed as much since it will need to travel only a short distance before it reaches the colon. There is also much less variability in the absorption in this fluid flow as it does not have to travel through most of the intestine before it reaches the colon. This greatly increasing control of stool hydration, and affords the ability to increase dose and efficacy.
Distribution of Guanylyl Cyclase C receptor in the intestine
According to the present invention, it is recognized that rational development of a formulation that provides the optimal site of action through modified release of compounds that activate GCC, would require knowledge of expression and activity levels of GCC protein throughout the intestine. The work of Krause (1994 a,b) and Qian (2000) describes the relative receptor density (Bmax fmole/mg protein) of GCC along the rostral-caudal axis of the intestine in Sprague-Dawley rats and newborn calves. As seen in FIG. 4, similar levels of GCC protein (STa-binding activity) are observed in the duodenum, cecum and colon of the rat. A complementary set of data from the newborn calf (FIG. 5) indicates an even higher level of GCC protein expression in the ileum relative to that observed in the colon (Al-Majali et al., 2000). Note: The divisions along the rostral-caudal axis in FIGS. 6 and 7 are based on those used in the paper by Qian et al., 2000. Prior to the present invention, conventional efforts have failed to develop a method of use for a formulation that provides modified release of compounds in the distal jejunum, ileum, cecum and proximal colon.
Guanylyl Cyclase C Receptor Affinity for STa (1-18)
An examination of affinity data (Ki) reveal similar affinities (1-4 nM Ki) for GCC expressed in the duodenum, cecum and colon. However, it should be noted (FIG. 6) that a 2 log decrease in the affinity of STa (1-18) for its receptor is seen for GCC expressed in the jejunum and cecum of the calf. This may be due to differences in GCC sequence homology between species.
In a study of human small intestine (n=20) and colon (n=24) specimens, Cohen (Gastroenterology, 1988) reported similar affinities for the interaction of STa (1-18) with GCC in these two tissues (1.9 nM and 1.2 nM, respectively). Although no correlation of receptor affinity with age (6 months to 16 years) was observed, Cohen did report a 75% decrease in the absolute expression of GCC with increasing age in this group. Furthermore, the level of GCC found in the small intestine relative to the colon increased as the patient population matured (small intestine:colon ratio of 0.9 at 6 months and a ratio of 1.8 at 15 years). Additionally, a log-linear increase in guanylyl cyclase activity was observed with increasing number of GCC receptors.
Distribution of Guanylyl Cyclase C Receptor Activity in the Intestine
Studies of GCC activity induced by incubation with STa (1-18) in human (Krause 1994) and rat (Cohen, 1989 and Qian, 2000) specimens supported Cohen's earlier findings (Cohen 1988) of a correlation of GCC protein expression with Guanylyl Cyclase activity. As was observed for GCC expression and affinity, high levels of GCC activity were observed in the proximal duodenum, ileum and colon, with reduced activity in the jejunum (as shown in FIG. 7).
Time Course of Guanylyl Cyclase C Activation
In separate studies examining the duration of response to STa (1-18) in intestinal loops, both Cohen (Cohen et al., 1989) and Nzegqwu & Levin (Nzegqwu & Levin, 1994) found a significantly longer duration of response in the Ileum relative to the jejunum (FIGS. 8a and 8b). The response in the ileum was also delayed compared to the response in the jejunum. Also of note is a study published by Shimonishi et al. (1987) demonstrating a significantly longer duration of response with Q-Cys5-STa (5-17) relative to its L-analog.
STa Peptides are Much More Stable in the Ileum than in the Duodenum
According to the present invention, there are additional reasons why the distal jejunum, ileum, cecum and proximal colon are the preferred targets for a GCCR agonist. Namely, STa peptides have been observed to have a half-life in the duodenum of about 3 minutes; compared to a half-life of about 30 minutes in the ileum (Al-Majali et al., 2007; Sellers et al., 2008; Kessler et al., 2008; Kessler et al., 2009). ST peptides are stable in the stomach but are rapidly degraded in the upper intestine. Linaclotide has been shown to be stable in simulated gastric fluid for up to 3 hours (Busby et al, 2010). However, linaclotide is degraded rapidly in the duodenum. In intestinal fluids from both mouse, rat and humans the peptide loses its C-terminal tyrosine and forms an active metabolite. The half life for linaclotide is 3 minutes in rat intestinal fluid and 1 minute in human intestinal fluid. This metabolite is also rapidly degraded, first by reductases and then by proteases. The half life for the metabolite is about 5 minutes in rat intestinal fluid, and 3 minutes in human intestinal fluid. It is not detectable after 60 minutes in rat intestinal fluid, and after 18 minutes in human intestinal fluid (Kessler et al., 2009; Kessler et al., 2008). Thus, if released in the stomach or duodenum, an ST peptide analogue such as linaclotide will be active only in the duodenum. It is likely that an uroguanylin analogue such as plecanatide is degraded even more rapidly and therefore has an even shorter activity time.
However, it has been observed that linaclotide is more stable in ileal intestinal fluid taken from the ileum than in fluid taken from the duodenum or jejunum. Kessler has shown that the half life in rat duodenal fluid was about 0.44 minutes, 0.36 in jejunal fluid, but about 30 minutes in ileal fluid (Kessler et al., 2008; Kessler et al, 2009). This correlates with the free thiol concentrations in these locations and the activity of the Glutathione Reductase/Glutareduxin system activities in these locations. Kessler also showed that both rat and human intestinal fluid has a high activity Glutathione Reductase/Glutareduxin system, and that the activity of the system in the human intestine is as high or higher than in the rat (Kessler et al., 2008; Kessler et al, 2009).
Lower level of thiols and reductases in ileal intestinal fluid predicts enhanced drug stability in ileum. Because of the higher concentration of reductases and thiol concentration in the duodenum and jejunum, as compared to the ileum, there is higher stability of STa peptides or uroguanylin peptides in the ileum. Thus, linaclotide is up to 100× more stable in ileal intestinal fluid due to a lower level of reductases compared to in the duodenum.
Improved Control of Stool Hydration Levels
Secretagogues (such as linaclotide and plecanatide) acting in the upper intestine have to introduce large amounts of fluid to affect colon stool fluid content. Most fluid introduced in the upper intestine is absorbed in the jejunum and ileum (Feldman et al., 2006, Bliss et al., 1999).
The colon is capable of enhancing fluid re-absorption in response to heightened ileo-cecal flow, which is a natural mechanism to avoid diarrhea. However, the colon is also sensitive to transient flows of fluid, as it may not always be able to adjust fluid absorption sufficiently fast. To overcome the absorption of fluid in the jejunum and ileum, and the regulation of fluid by the colon, and add net water to the stool, the effect of a duodenally-acting secretagogue must be considerable, adding in upwards of 3 liters of fluid. Most of this fluid will be absorbed in the small intestine. However, the natural variability in absorption, enhanced by the extra fluid flow, creates swings in stool fluid content after treatment with a secretagogue that acts in the duodenum or upper jejunum. The resulting titration of fecal fluid will be imprecise and results in wide swings in net fecal water. Moreover, the colon may not be able to adjust quickly enough to transient increases in fluid flow, further increasing the likelihood of diarrhea.
The incidence of diarrhea after linaclotide treatment can range between 13% and 20%, narrowing the therapeutic window and efficacy for the compound. Numerous patients actually dropped out of clinical studies with linaclotide because of diarrhea (Lembo et al., 2010a; Lembo et al., 2010b; Ironwood Pharmaceuticals 2010). This is worrisome, as efficacy and tolerability typically drop further as drugs are translated from clinical trials to medical practice. With regard to clinical results observed with linaclotide, the primary efficacy endpoint of three or more CSBMs per week and an increase of at least one CSBM per week over baseline for at least nine of the 12 weeks of the treatment period was achieved by only 21% of patients (Bryant et al., 2010).
For at least these reasons, a secretagogue drug (such as linaclotide or plecanatide) that is released in the stomach, duodenum or proximal jejunum is acting in a less suitable site for stool hydration therapy and has several disadvantages compared to drugs that drug that are released in the distal jejunum, ileum or in the proximal colon. In the case of treatment with a secretagogue such as an ST peptide drug or a uroguanylin peptide drug that is released in the stomach or the duodenum, the small bowel and colon are required to reabsorb a large fluid load secreted by the duodenum in order to hydrate the stool; this is a very inefficient system prone to error (i.e. diarrhea). Moreover, any downward adjustment of the dose of drug to avoid diarrhea would result in reduced efficacy, and the merits of treating CIC and IBS with a GCCR agonist will not be fully realized.
In practice, patients will over-dose and under-dose secretagogues and similar-acting drugs. This has been the exact experience in the past with cathartic drugs sold over the counter. However, due to the imprecise control of stool hydration afforded with a GCCR agonist acting in the duodenum or proximal jejunum, it will be difficult for patients to achieve optimum effect. A drug with a more optimal therapeutic window (efficacy vs. tolerability) is therefore still needed (Bharucha & Waldman, 2010).
Unexpected Advantages of Slow Release Formulations
Slow release formulations of the present invention have unexpected advantages. The intestine, including the colon, has a limited capacity to absorb high transient fluid flows. Immediate release formulations of secretagogues can therefore lead to fluid flows that cannot be absorbed and that can cause diarrhea. If the drug is instead released slowly, over a time period between 1 hour and up to 8 hours, the fluid flow can instead be managed by the intestine, causing a slow and manageable increase in stool hydration. This will cause less swings in stool hydration and a more manageable and titratable therapeutic effect.
Unexpected Advantages of the Ileal-Cecal-Colon Site of Action of the Present Invention
The ileal, cecal or colon release formulations of the present invention, preferably distal jejunum, ileal or proximal colon slow-release formulations, are predicted to achieve many more significant and unexpected advantages compared to conventional approaches, including unexpected improvement in efficiency of stool hydration and improved colonic fluid content regulation.
The unexpected advantages of stool hydration therapy of the present invention obtained from e.g., the ileal slow-release formulations, include, for instance, inducing a sustained flow of fluid resulting from low levels of secretion in the most sensitive end-organ (i.e. the colon).
Formulations of at least one such compound of the present invention, SEQ ID NO 60, are predicted to be several-fold more effective when released in the distal jejunum, ileum and colon; and small amounts of the drug (SEQ ID NO 60) can be titrated to effect a sensitive dose response. Moreover, the therapeutic window will be improved with such a slow release formulation, leading to better therapeutic response and lower rates of diarrhea and drug discontinuation, and higher rates of efficacy and tolerability, especially in the elderly, an important target population for these agents.
Also, techniques for preparing controlled-release, delayed-release, and/or slow-release formulations (e.g., for release in the ileum) can be employed, which techniques are well known in the art for other types of pharmaceutical compounds (e.g., see Remington, J P. Remington's Pharmaceutical Sciences. Mack Pub. Co.; 16th edition; 1980).
Further Advantages of the Stool Hydration Agents of the Present Invention
The agents of the present invention can be delivered to the stomach, duodenum, jejunum, ileum and colon, and will be therapeutically active there. However, the exemplary stool hydration agent acts on the target organ; the colon. According to the present invention, the most sensitive and optimal place to effect a controlled change in stool and water absorption/secretion is the distal jejunum, ileum, cecum and proximal colon, not the stomach, duodenum or proximal jejunum.
Creating an environment of secretion in the proximal intestine would be the least efficient means one could develop to adjust intestinal fluid content and improve end-stool consistency; the mechanism would be inherently prone to uncontrolled swings of excess fluid output (i.e., diarrhea).
Instead, according to the present invention, the ideal stool hydration agent works in the distal jejunum, ileum, cecum and proximal colon by introducing small amounts of fluid over an extended period of time. As a result, a small amount of fluid avoids disturbing the colon into generating diarrhea. Also, introduction of the ileal-release formulation over time permits an extended section of stool to be hydrated.
Although targeting the distal jejunum, ileum, cecum and proximal colon is preferred, this is not to exclude embodiments of the present invention that target other parts of the GI tract such as the stomach, duodenum or proximal jejunum. The compounds of the present invention will be therapeutically active in those other parts of the GI tract, although with disadvantages as discussed above.
Improvement in Fluid Regulation in the Colon
FIG. 9 depicts an overview of normal fluid regulation in the colon (no drug treatment). The text in FIG. 9 refers to the number references in the FIG. 1) Approximately 9 L of fluid enters the upper small bowel each day from ingestion (2 L), saliva (1.5 L), gastric secretion (2 L), bile (0.5 L), pancreatic secretion (1.5 L) and intestinal secretion (1.5 L). 2) Of this, approximately 7.5 L is absorbed in the small bowel (jejunum and ileum). 3) Only about 1.5 L enters the colon. 4) Over 90% of this ileo-cecal fluid flow is absorbed there. Only about 100 cc of fluid is excreted in the stool. The colon is the main control point for stool hydration and composition. It can augment absorption in response to an increase in the fluid flow, but only up to about 3× increase. It is also sensitive to transient high fluid flows, which can cause “breakthrough” diarrhea. 5) Normal stool contains about 100 to 200 cc of fluid excreted per day. Less than 50 cc excretion per day is indicative of constipation, while more than 200 cc per day is indicative of diarrhea. Thus, the difference between hard and soft stool is quite small, about 30 cc (Feldman et al., 2006; Aichbichler et al., 1998; Bliss et al., 1999).
FIG. 10 depicts an overview of the fluid regulation system in the colon after administration of an ST or Uroguanylin peptide drug that is released in the stomach or duodenum (Feldman et al., 2006; Aichbichler et al., 1998; Bliss et al., 1999; Bryant et al., 2010; Busby et al., 2010). A GCC peptide drug (such as linaclotide or plecanatide) that is released in the stomach or will be stable there (ST and Uroguanylin peptides are usually acid stable). Once it enters the intestine it will be rapidly broken down, with a half life in the intestine of about 5 minutes in total (including active metabolites) and be active for about 15 minutes. The main site of drug activity will therefore be in the duodenum. A GCC peptide drug that is released in the duodenum will have a similar half life and activity period once it is released. This will result in wide swings of fluid secretion in response to pharmacologic stimulation as described above.
By comparison, FIG. 11 depicts an overview of the fluid regulation system in the colon after administration of a formulation that releases the secretagogue drug in the region of the distal jejunum, ileum, cecum and/or proximal colon, in accordance with the present invention. As described herein, this type of release formulation offers numerous unexpected advantages, including a safer, more effective and more controllable mechanism for hydrating the stool. By acting close to the end organ (colon), less net secretion is needed to hydrate the stool. This represents a safer, more effective and more controllable mechanism to hydrate the stool. (Feldman et al., 2006; Aichbichler et al., 1998; Bliss et al., 1999; Bryant et al., 2010; Busby et al., 2010).
Improvement in Colonic Fluid Content Regulation
FIG. 12 depicts colonic fluid content regulation after administration of a conventional stomach or duodenal releasing secretagogue drug. The large swings in stool fluid content that are caused by the drug require the dose to be lowered, reducing the response rate to the treatment.
By comparison, FIG. 13 depicts colonic fluid content regulation after administration of a releasing drug formulation that releases the drug starting in the distal jejunum, ileum, cecum and/or proximal colon, in accordance with the present invention. As illustrated, extended release in this region permits a more controlled increase in stool fluid content. Slow release of the secretagogue drug closer to the target organ (colon) requires the secretion of less fluid since less fluid will be absorbed before the drug reaches the colon. This in turn provides better control of fluid flow, less swings in stool hydration and better control of therapeutic effect. This in turn results in higher therapeutic response rates.
Additional Features of the Formulations of the Present Invention Designed to Release in the Distal Jejunum, Ileum, Cecum and/or Proximal Colon
According to another embodiment of the invention, the target product profile for the distal jejunum, ileal, cecal and/or proximal colonic releasing formulations of the invention can be used in the design of the formulations. Also, knowledge about GI tract physiology, GCC receptor distribution in the intestinal tract, and reductase distribution, are also used in formulation design.
FIG. 14 illustrates one example of a formulation designed to start releasing in the distal jejunum, in accordance with the present invention. The design can also be intended to release the drug over a time period of between 1 and 24 hours. Such formulation design criteria include, but are not limited to, a pH dependent coat; a slow-release core; bead formulation to disperse the active ingredient in the intestine; use of a capsule or tablet matrix; and one or more excipients to stabilize the active ingredient. Release of a ST peptide or Uroguanylin drug in this region will result in longer activity due to longer half life (Kessler et al., 2008; Kessler et al., 2009). In addition, longer activity of the drug can also be achieved by incorporating design features in the formulation that protect the drug from the intestine environment until it is released. Other profiles can start the release in the ileum, cecum and/or proximal colon. The time profile of the release can also be varied, with release occurring over a time period between 1 and 24 hours.
Constipation is a multifaceted condition, but stool hydration provides relief in the vast majority of patients. As described further herein, the present invention provides unexpected advantages with regard to improved stool hydration.
FIG. 15 depicts a summary of intestine fluid flow and stool hydration control under normal conditions, as compared to constipation. As shown, the difference between constipation and normal stool is as little as 30 to 50 cc of fluid content in the stool per day. This provides a narrow target for a stool hydration agent, and control of stool fluid content is therefore an important consideration for these types of therapeutics. As depicted in part A of FIG. 15, the intestine secretes and absorbs large amounts of fluids daily, with the absorption taking place in the small intestine and fine control of stool fluid content taking place in the distal colon. Part B of FIG. 15 depicts stool fluid content in the stool over 7 days, normal and constipated. Normal stool stays in a tight range of hydration, about 100 to 200 cc per day. Constipation occurs when stool is hydrated 30 to 50 cc to little.
FIG. 16 shows that treatment with a secretagogue that is released in the stomach or duodenum is associated with large swings in stool fluid content. To add 30 cc of fluid to the stool, a drug that is released in the stomach or duodenum must induce secretion of up to 3 liters in the duodenum. Part A of FIG. 16 depicts daily fluid flow through the intestine where a stomachally or duodenally acting agent is used. To affect a small difference in the stool, a duodenally acting agent must induce secretion of a large amount of fluid. This is dictated by the physiology of the gastrointestinal tract. Part B of FIG. 16 depicts stool fluid content in the stool over 7 days where a stomachally or duodenally acting agent is used. Natural variability in re-absorption will result in large swings in stool fluid content. Titration of fecal fluid will be imprecise, resulting in over- and under-treatment. To avoid this, the dose of the drug must be lowered, resulting in a lower overall response rate.
FIG. 17 shows that an ileal slow release formulation, in accordance with the present invention, unexpectedly and surprisingly allows much better control of stool hydration, resulting in higher clinical response rates. A stool hydration agent should ideally act in the target organ; the colon. Much less net secretion will be needed to hydrate the stool. Part A of FIG. 17 depicts daily fluid flow through the intestine where an ileal slow release formulation is used. Part B of FIG. 17 depicts stool fluid content in the stool over 7 days where an ileal slow release formulation is used. Tighter control of stool hydration permits more precise dose titration with a resulting higher response rate. Thus, an ileal slow release formulation allows much better control of stool hydration, resulting in higher clinical response rates, in accordance with the present invention.
It is to be understood that any suitable excipients, dosage forms, and range of concentrations can be employed to prepare the formulations contemplated by the present invention. Representative excipients, dosage forms, and concentrations can be selected to achieve the desired properties of the formulation. Exemplary excipients include, but are not limited to, stabilizing agents; solubilizing agents; diluents; binders; lubricants; etc. Thus, the peptides can be included in a unit dose form, together with suitable carriers, excipients and diluents. As used here the term unit dose form refers to a single delivery vehicle, such as a tablet, capsule, solution or inhalation form. The peptides may also be formulated to be delivered together in combination with another pharmacological agent in the same unit. It is also to be understood that the examples described herein are merely used to illustrate certain embodiments of the invention, but are in no way intended to limit the scope of the invention.
Controlled Slow Release Formulation
In one embodiment, GCC peptide formulations comprise a composition which provides a controlled release (e.g. time-dependent, pH-dependent, temperature-dependent, ionic strength-dependent, viscosity-dependent) of the GCC peptide. Controlled release may mean delayed sustained release, delayed controlled release, delayed slow release, delayed prolonged release, delayed extended release, and sudden release or several sudden releases (or “bursts”) at differing times or locations.
Examples of controlled formulations are where a slowly disintegrating core comprising the GCC peptide is surrounded by the targeting composition. The targeting composition preferably comprises at least one swellable polymer. Non-limiting examples of such polymers are acrylic copolymers, e.g., EUDRAGIT RL, EUDRAGIT RS, or EUDRAGIT NE; polyvinylacetate, e.g., KOLLICOAT SR 30D; and cellulose derivatives such as ethylcellulose or cellulose acetate, e.g., SURELEASE and AQUACOAT ECD, poly(hydroxalkyl methacrylate) having a molecular weight from 20,000 to 5,000.000; kappa-carrageenan; polyvinylpyrrolidone having a molecular weight of from 10,000 to 500,000; anionic and cationic hydrogels; polyelectrolyte complexes; poly(vinyl alcohol) having low amounts of acetate, cross-linked with glyoxal, formaldehyde, or glutaraldehyde and having a degree of polymerization from 200 to 30,000; a water-insoluble, water-swellable copolymer produced by forming a dispersion of maleic anhydride with styrene, ethylene, propylene or isobutylene; water-swellable polymers of N-vinyllactams; polysaccharidc, water swellable gums and/or mixtures thereof, cross-linked polysaccharide, water insoluble starch, calcium pectinate, microcrystalline cellulose, water insoluble crosslinked protein, water insoluble cross-linked gelatin, water insoluble cross-linked collagen, and cross-linked polyacrylic acid, disintegrants such as microcrystalline cellulose, kaolin, titanium dioxide, fumed silicon dioxide, alumina, niacinamide, sodium lauryl sulfate, low molecular weight polyvinyl pyrrolidone, m-pyrol, bentonite, magnesium aluminum silicate, polyester, and mixtures thereof.
The formulation may also comprise a water insoluble polymer and a pore-forming agent. Non-limiting examples include saccharose, sodium chloride, potassium chloride, polyethyleneglycol, water soluble organic acids, sugars and sugar alcohol.
The formulation may also comprise a compression coating. Non-limiting examples are xanthan gum, locust bean gum, galactans, mannans, alginates, gum karaya, tragacanth, agar, accacia, carrageenan, chitosan, agar, hydrocolloids acacia catechu, salai guggal, copaiba gum, asafetida, cambi gum, mastic gum, benzoin gum, sandarac, gambier gum, guar gum, welan gum, gellan gum, tara gum, locust bean gum, carageenan gum, glucomannan, galactan gum, sodium alginate, tragacanth, chitosan, xanthan gum, deacetylated xanthan gum, pectin and cultured plant cell gums, as well as mixtures thereof.
The formulation may also include a suspending agent, a plasticizer, a stiffening agent, a wetting agent, a or a dispersing agent, or combinations thereof. Non-limiting examples are dibutyl sebacate, polyethylene glycol and polypropylene glycol, tributyl citrate, acetylated monoglyceride, acetyl tributyl citrate, triacetin, dimethyl phthalate, benzyl benzoate, butyl and/or glycol esters of fatty acids, oleic acid, castor oil, camphor, glycerol and sorbitol or a combination thereof.
The formulation may also include a wetting agent. Non-binding examples include poloxamer, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxymethylene stearate, sodium lauryl sulfate, and docusate sodium. The formulation may also include a suspending agent. Non-limiting examples include alginic acid, bentonite, carbomer, carboxymethylcellulose, carboxymethylcellulose calcium, hydroxyethylcellulose, colloidal silicon dioxide, dextrin, gelatin, guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol, sodium alginate, sorbitan fatty acid esters, and tragacanth. The formulation may also include a dispersing agent. Non-limiting examples for dispersing agents are poloxamer, polyoxyethylene sorbitan fatty acid esters and sorbitan fatty acid esters.
The targeted release composition may contain an outer enteric coating over the targeted release material. Such coatings may be selected from the group consisting of cellulose acetate phthalate, hydroxy propyl methyl cellulose acetate succinate, and various EUDRAGIT polymers, or combinations thereof.
The GCC peptide formulation may comprise of one or more natural or synthetic biodegradable polymers and/or pH-dependent release formulations. Non-binding examples include amethacrylic acid copolymers, polyvinyl acetate phthalate, hydroxypropylmethylcellulose, cellulose acetate trimelliate, or hydroxypropyl methyl cellulose acetate Succinate, EUDRAGIT polymers, or combinations thereof.
Sudden Release Formulation
In one embodiment, the GCC peptide formulation may be a time-delayed formulation, designed to release the GCC agonist in a fast burst in the colon or small intestine. These formulations may include at least one disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, calcium carboxymethyl cellulose, and magnesium aluminum silicate, at least one of an absorption enhancer, a binder, a hardness enhancing agent, a buffering agent, a filler, a flow regulating agent, a lubricant, a dispersant, a chelator, an antioxidant, a stabilizer, a preservative, and one or more other excipients.
Examples
3 types of experiments were carried out to determine relative potency and efficacy:

    
    
        Competitive 125I-labeled radioligand binding on mouse intestine
        cGMP accumulation assay
        Mouse intestinal secretion assay (suckling mouse assay)
    
    


The peptides were also analyzed using standard HPLC and LCMS methodologies.
Example Peptides Used in the Experiments
The above-described experiments were performed using the following peptides:







STa (1-18) (ST) SEQ ID NO: 28):


H2N Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro


 


Ala Cys Ala Gly Cys Tyr COOH


 


Linaclotide (SEQ ID NO: 40):


H2N Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly


 


Cys Tyr COOH


 


Peptide A (A) (SEQ ID NO: 60):


H2N Cys Cys Glu Leu Cys Cys Asn Dhp Ala Cys Ala Gly


 


Cys Tyr COOH


 


Peptide B (B) (SEQ ID NO: 61):


H2N Cys Cys Glu L-Thr Cys Cys Asn Pro Ala Cys Ala


 


Gly Cys Tyr COOH


 


Peptide C (C)(SEQ ID NO: 62):


H2N Cys Cys Glu Leu Cys Cys Asn HyPro Ala Cys Ala


 


Gly Cys Tyr COOH


 


Peptide D (D) (SEQ ID NO: 63):


H2N Cys Cys Glu Leu Cys Cys Asn Thz Ala Cys Ala Gly


 


Cys Tyr COOH













TABLE 9







Summary of experimental data for peptides.











I-125 
CGMP
Mouse intestinal



binding
accumulation
secretion assay


Peptide
assay
assay
(suckling mouse)





STa(1-18)
+++
++++
++++


Linaclotide
+++
+++
+++


A
+++++
+++++
+++++


B
++++
+++
+++


C
++
+++
NM


D
+++++
+++++
+++++





Results are graded from 1+ (lowest activity/potency) to 5+ (highest activity/potency). NM is “not measured”.






Intestinal membrane 1-125 labeled radioligand binding assay. The intestinal membrane radioligand binding assay was used to assess whether a novel compound could displace 125I-STa from GC-C (Crane et al., 1992). Each analog was analyzed for its ability to displace 125I-STa from GC-C in a competitive binding assay. 125I-ST Displaced” was determined by co-incubating STa analogs (10 μM) with 50,000 DPM of 125I-STa (1-18) in the presence of mouse intestinal membranes. The displacement (n=3) for each analog was determined relative to a vehicle control.
Membrane and Tissue Homogenate Preparation:
Membranes were prepared from freshly harvested mouse intestines by first washing away the blood or feces with ice-cold Dulbecco's PBS. Washed organs were minced with a single-edged razor blade, followed by homogenization on ice in 50 mM Tris, pH 7.6, containing 1 mM EDTA, 1 mM PMSF, 1 mM DTT. Debris was then removed by a 15 minute centrifugation at 3,000×G and 4° C. The supernatant is then passed through successively smaller needles (18 gauge through 25 gauge) and frozen at −70° C. until used as a tissue homogenate. If intended for use as isolated membranes, the above homogenate was centrifuged (100,000×G) at 4° C. for 1 hour while fresh and the pellet was re-suspended in homogenization buffer.
Competitive Radioligand Binding Assay:
The assay was performed in 96 well filter plates which were pre-incubated overnight with 200 μl of 0.3% polyethylenimine (w/v) and washed three times by aspiration with 300 μl of Wash Buffer (150 mM NaCl, 20 mM Sodium Phosphate pH=7.2, 1 mM EDTA) immediately before use. Into each well of was added 50 μl of 3× Binding buffer (150 mM Tris-HCl pH=7.6, 1.98 mM Cysteamine, 0.3% Bacitracin, 1350 mM NaCl, 3 mM EDTA), 40 μl of double-distilled water, 10 μl of either double-distilled water or cold ligand (50 uM STa (5-18) in double-distilled water), 10 μl of increasing concentrations (125 DPM/ul to 50,000 DPM/ul) of radiolabeled 125I -STa (1-18) and finally 40 μl (approximately 2 mg protein/ml) of freshly prepared mouse intestine membranes. The plates were then incubated with mixing at 37 C for two hr, washed successively with six 200 μl aliquots of Wash Buffer and aspirated to dryness. The filter bottoms of each well were punched into individual borosilicate tubes and bound radioactivity determined in a gamma counter. Protein content was determined on an aliquot of the mouse intestine membranes used in the Biorad Protein Assay.
Results:
FIG. 18 shows the activity of two different ST peptides of the invention, peptide A (SEQ ID NO 60) and peptide B (SEQ ID NO 61), compared to linaclotide (SEQ ID NO 40) and the natural STa peptide (SEQ ID NO 28), in the 1-125 labeled radioligand binding assay, as described above. In this example peptide B had an activity comparable to STa, and peptide A had a better activity than STa.
FIG. 19 shows the activity of peptide A (SEQ ID NO 60) compared to linaclotide (SEQ ID NO 40) in the 1-125 labeled radioligand binding assay, as described above. In this example peptide A had a superior activity compared to linaclotide.
FIG. 20 shows the activity of peptide A (SEQ ID NO 60), peptide C (SEQ ID NO 62) and peptide D (SEQ ID NO 63)), compared to linaclotide (SEQ ID NO 40) and ST peptide (SEQ ID NO 28), in the 1-125 labeled radioligand binding assay, as described above. In this experiment, peptides A and D had an activity that was superior to ST peptide, while peptide C had an activity that was comparable to ST peptide.
FIG. 21 shows the activity of peptide A (SEQ ID NO 60) and peptide B (SEQ ID NO 61), compared to linaclotide (SEQ ID NO 40), in the 1-125 labeled radioligand binding assay, as described above. In this experiment, peptides A had an activity that was superior to linaclotide, while peptide C had an activity that was lower than linaclotide.
Intact T84 Cell cGMP Accumulation Assay (cGMP Assay):
The intact T84 cell assay was used to detect the accumulation of cGMP, the product of agonism, upon interaction with a compound (Visweswariah et al., 1992). Human colorectal adenocarcinoma T84 cells were grown to confluence in a 24 well plate using DMEM/F12 medium supplemented with 10% FBS. The media was aspirated from each well and the cells were washed three times with Dulbecco's PBS (1×, no Ca2+ or Mg2+). The cells were then incubated for 30 minutes at 37° C. with 1 mM isobutyryl methyl xanthine (IBMX) in Optimem medium (no FBS), either with or without potential antagonists. After incubation under these conditions, a 10× concentrated stock of a known GC-C agonist (e.g., STa (5-18)) in PBS was added to each well and the incubation continued for an additional 15 min at 37° C.
cGMP Radioimmunoassay:
The reaction was stopped by the addition of 200 μL of Passive Lysis Buffer (Promega) to each well. The supernatant was removed for cGMP quantitation by RIA using 125I-labeled cGMP 54 antibody relative to an external cGMP standard curve. The cells were scraped from the surface for protein content determination using a BioRad Protein Assay.
Results:
FIG. 22 shows the activity of peptide A (SEQ ID NO 60) compared to linaclotide (SEQ ID NO 40) and STa (SEQ ID NO 28) in the cGMP accumulation assay as described above. In this experiment peptide A had an activity that was higher than the STa peptide, while the activity of linaclotide was lower than the STa peptide.
FIG. 22 shows the activity of peptides A (SEQ ID NO 60), B (SEQ ID NO 61), C (SEQ ID NO 62) and C (SEQ ID NO 63), compared to linaclotide (SEQ ID NO 40) and STa (SEQ ID NO 28) in the cGMP accumulation assay as described above. In this experiment peptide A and D had an activity that was higher than the STa peptide, while the activity of peptide B, C and linaclotide was lower than the STa peptide.
Mouse Intestinal Secretion Assay (Suckling Mouse Assay)
A relevant disease model is the suckling mouse model in which STa (5-18) is deposited into the stomach of 3-4 day old mice, and the accumulation of fluid in their intestines is determined gravimetrically (Parkinson et al., 1994). All GCC peptides were formulated to the desired concentration in Dulbecco's PBS (1×, No Ca++, no Mg++) containing 1 methylene blue immediately prior to dosing. Proteinase inhibitors were prepared as stock solutions in PBS and added to dosing solutions by serial dilution, as needed. The dosing solution (50 μL) was delivered into the stomachs of 2-4 day old mice (3 per dosing group) using a plastic tube attached to the needle of a 1 mL tuberculin syringe. After 3 hours, the animals were sacrificed and dissected to determine the individual weights of the intestines and the rest of the carcass, respectively.
Results:
FIG. 24 shows a bar graph of the results from a mouse intestinal secretion assay (as described above) of peptide A (SEQ ID NO 60) compared to linaclotide (SEQ ID NO 40). In this assay peptide A had better activity than linaclotide.
FIG. 25 shows a the activity of peptide A (SEQ ID NO 60) compared to STa peptide (SEQ ID NO 28) in the mouse intestinal secretion assay, as described above. In this experiment peptide A had higher activity than the STa peptide.
FIG. 26 shows a the activity of peptidase A (SEQ ID NO 60), B (SEQ ID NO 61) and D (SEQ ID NO 63), compared to STa peptide (SEQ ID NO 28) and linaclotide (SEQ ID NO 40) in the mouse intestinal secretion assay, as described above. In this experiment peptide A had higher activity than the STa peptide. In this experiment, peptides A and D had higher activity than STa, while peptide B and linaclotide had lower activity.
HPLC Analysis of the Peptides
The peptides were analyzed through standard HPCL and LCMS methodologies. FIGS. 27 to 30 shows chromatograms of peptides A through D (SEQ ID NO 60 through 63). HPLC analysis: The peptides were analyzed by standard High Performance Liquid Chromatography (HPLC) using a Vydac C18 column (4.6 mm×150 mm, 5 microns) with a Tri Fluoro Acetic acid buffer system at 30° C.
Results:
FIG. 27 shows the HPCL analysis of peptide A (SEQ ID NO 60). The analysis shows only one significant peak in the sample and indicate that the peptide is 98% pure.
FIG. 28 shows the HPCL analysis of peptide B (SEQ ID NO 61). The analysis shows only one significant peak in the sample and indicate that the peptide is 97% pure.
FIG. 29 shows the HPCL analysis of peptide C (SEQ ID NO 62). The analysis shows only one significant peak in the sample and indicate that the peptide is 95% pure.
FIG. 30 shows the HPCL analysis of peptide D (SEQ ID NO 63). The analysis shows only one significant peak in the sample and indicate that the peptide is 99% pure.

## Claims

1. A peptide comprising the amino acid sequence of SEQ ID NO: 60.

2. The peptide of claim 1, further comprising a pharmaceutical carrier, excipient or diluent.

3. The peptide of claim 1 formulated in a unit dose form.

4. The peptide of claim 3, wherein the unit dose form is a powder, a tablet, a capsule, a tablet matrix, a suppository, a controlled release formulation, a delayed release formulation, a slow release formulation, a sustained release formulation, a colonic release formulation, an oral formulation, a bead formulation, a microencapsulated delivery system, a fluid carrier, a solution, a gelatin capsule, or a liposomal suspension.

5. The pharmaceutical composition of claim 4, wherein the unit dose form is a controlled release formulation.

6. A method for treating a disease or a disorder, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a peptide comprising the amino acid sequence of SEQ ID NO: 60, wherein the disease or disorder is selected from the group consisting of constipation, chronic idiopathic constipation, irritable bowel syndrome with constipation, opioid induced constipation, post-surgical constipation.

7. A peptide comprising the amino acid sequence of SEQ ID NO: 63.

8. The peptide of claim 7, further comprising a pharmaceutical carrier, excipient or diluent.

9. The peptide of claim 7 formulated in a unit dose form.

10. The peptide of claim 9, wherein the unit dose form is a powder, a tablet, a capsule, a tablet matrix, a suppository, a controlled release formulation, a delayed release formulation, a slow release formulation, a sustained release formulation, a colonic release formulation, an oral formulation, a bead formulation, a microencapsulated delivery system, a fluid carrier, a solution, a gelatin capsule, or a liposomal suspension.

11. The pharmaceutical composition of claim 10, wherein the unit dose form is a controlled release formulation.

12. A method for treating a disease or a disorder, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a peptide comprising the amino acid sequence of SEQ ID NO: 63, wherein the disease or disorder is selected from the group consisting of constipation, chronic idiopathic constipation, irritable bowel syndrome with constipation, opioid induced constipation, post-surgical constipation.