Patent Publication Number: US-5252705-A

Title: Peptide derivatives

Description:
FIELD OF ART 
     The present invention relates to novel peptide derivatives. In more particular, it relates to parathyroid hormone antagonists. 
     BACKGROUND OF THE INVENTION 
     Parathyroid hormone (referred to as PTH hereinafter) is a peptide hormone consisting of 84 amino acid residues, which is responsible for bone and calcium metabolism. A peptide fragment consisting of the first to 34th amino acid residues at the N-terminal of PTH, which is called PTH (1-34), has the same biological activity as PTH. On the other hand, other peptide fragments which lack the first few N-terminal amino acid residues, PTH (3-34), PTH (7-34), and the like, are known to suppress PTH activity. 
     Recently, it has been found that a PTH-related peptide (referred to as PTHrP hereinafter) derived from human carcinoma exhibits biological activity similar to PTH, and its chemical structure has been determined (Suva et al, Science, Vol.237, 893, 1987). The human PTHrP is a polypeptide consisting of 141 amino acid residues. It has biological activity similar to that of PTH, such as elevation of blood calcium level, acceleration of born absorption, lowering of blood phosphorous level, lowering of urinary calcium level, increasing of urinary cAMP level, and activation of hydroxylase at the 1-position of vitamin D in kidney (Horiuchi et al, Science, Vol.238, 1988; Kemp et al, Science, Vol.238, 1988). 
     Primary structure of PTHrP has poor similarity to that of PTH although partial structure of PTHrP at the amino terminal shows similarity to that of PTH. In spite of the fact, fragments of PTHrP, which lack a few amino terminal residues, such as PTHrP (3-34), suppress PTH activity likewise in PTH (Rabbani et al, oral speech at the meeting of the America Bone Metablism Association, 1988). 
     PTH derivatives such as [Tyr 34  ]-hPTH (3-34)-NH 2  and PTHrP derivatives such as hPTHrP (3-34)-NH 2  are known as a PTH antagonist. However, there has been a need to discover move potent PTH antagonist activity. The present invention relates to the peptides consisting of 25-50 amino acid residues and comprising the following peptide sequence, and amides and salts thereof. 
     
         Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile (Seq Id No. 1)                    (I) 
    
     The following abbreviations are used in this text. 
     Asp: aspartic acid 
     Thr: threonine 
     Ser: serine 
     Asn: asparagine 
     Gln: glutamine 
     Glu: glutamic acid 
     Gly: glycine 
     Ala: alanine 
     Met: methionine 
     Ile: isoleucine 
     Leu: leucine 
     Phe: phenylalanine 
     Lys: lysine 
     His: histidine 
     Arg: arginine 
     Boc: t-butoxycarbonyl 
     Z: benzyloxycarbonyl 
     OcHx: cyclohexyl ester 
     OBzl: benzyl ester 
     Bzl: benzyl 
     Tos: p-toluenesulfonyl 
     Cl-Z: 2-chlorobenzyloxycarbonyl 
     The peptide derivatives of the present invention contain at least the peptide sequence represented by the formula (I) mentioned above. For instance, the peptide derivatives of the invention may be represented by the following formula (II): 
     
         X-Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-Y-z                             (II) 
    
     wherein X represents H, (Seq. ID Nos: 2-5), H-Gln (Seq. ID Nos: 6-9), H-A-Gln, (Seq. ID Nos. 6-9) H-Glu-A-Gln- (Seq. Id. Nos: 14-17), or Ser-Glu-A-Gln- (Seq. ID Nos: 18-21), wherein A is Ile, Thr, Val, or Leu; Y represents His-Thr-Ala, His-Thr-Ala-Glu-Ile-Arg-Ala, His-Thr-Ala-Glu-Ile-Arg-Ala-Thr-Ser-Glu-Val, His-Thr-Ala-Glue-Ile-Arg-Ala-Thr-Ser-Glu-Val-Ser-Pro-Asn-Ser-Lys-Pro-Asn; Z represents OH or NH 2 . 
     The following Table 1 lists specific examples of the peptide derivatives of the invention. 
     
                                           TABLE 1                                 
__________________________________________________________________________
X--Leu--Met--His--Asn--Leu--Gly--Lys--Ser--Ile--Gln--Asp--Leu--Arg--Arg-- 
Arg--Phe--Phe--Leu--His--His--Leu--Ile--Ala--Glu--Ile--Y--Z               
Compound                                                                  
No.   X            Y           Z                                          
__________________________________________________________________________
1     H--Ser--Glu--Ile--Gln                                               
                   His--Thr--Ala                                          
                               NH.sub.2                                   
                                  (SEQ ID NO: 18)                         
2     H--Glu--Ile--Gln                                                    
                   His--Thr--Ala                                          
                               NH.sub.2                                   
                                  (SEQ ID NO: 14)                         
3     H--Ile--Gln  His--Thr--Ala                                          
                               NH.sub.2                                   
                                  (SEQ ID NO: 10)                         
4     H--Gln       His--Thr--Ala                                          
                               NH.sub.2                                   
                                  (SEQ ID NO: 6)                          
5     H            His--Thr--Ala                                          
                               NH.sub.2                                   
                                  (SEQ ID NO: 2)                          
6     H--Ser--Glu--Ile--Gln                                               
                   His--Thr--Ala                                          
                               OH (SEQ ID NO: 18)                         
7     H--Ser--Glu--Ile--Gln                                               
                   His--Thr--Ala--Glu--                                   
                               NH.sub.2                                   
                                  (SEQ ID NO: 19)                         
                   Ile--Arg--Ala                                          
8     H--Ser--Glu--Ile--Gln                                               
                   His--Thr--Ala--Glu--                                   
                               NH.sub.2                                   
                                  (SEQ ID NO:20)                          
                   Ile--Arg--Ala--Thr--                                   
                   Ser--Glu--Val                                          
9     H--Ser--Glu--Ile--Gln                                               
                   His--Thr--Ala--Glu--                                   
                               NH.sub.2                                   
                                  (SEQ ID NO: 21)                         
                   Ile--Arg--Ala--Thr--                                   
                   Ser--Glu--Val--Ser--                                   
                   Pro--Asn--Ser--Lys--                                   
                   Pro--Asn                                               
10    H--Ser--Glu--Val--Gln                                               
                   His--Thr--Ala                                          
                               NH.sub.2                                   
                                  (SEQ ID NO: 18)                         
11    H--Ser--Glu--Thr--Gln                                               
                   His--Thr--Ala                                          
                               NH.sub.2                                   
                                  (SEQ ID NO: 18)                         
12    H--Ser--Glu--Leu--Gln                                               
                   His--Thr--Ala                                          
                               NH.sub.2                                   
                                  (SEQ ID NO: 18)                         
__________________________________________________________________________
 
    
     The peptide derivatives of the invention may be used after conversion to pharmacologically acceptable salts thereof, such as hydrochloride or acetate. 
     The PTHrP derivatives of the invention represented by the formula (I) or (II) may be prepared by repeating condensation reaction between relevant protected amino acids by means of conventional solid phase method, said reaction being sequentially conducted starting from C-terminal and according to the amino acid sequence shown in formula (I) or (II), and removing the protective groups and carrier to which the C-terminal amino acid residue has been linked by known methods such as acid decomposition and aminolysis. The peptide synthetic method mentioned above and the starting amino acid derivatives used therein are described in detail in various text books (See Izumiya et al, &#34;Basis and Practice of Peptide Synthesis&#34;, published by Maruzen, 1985; Gross and Meienhofer&#39;s, &#34;The Peptides&#34;, Vol.2, Academic Press, 1980). 
     The solid phase carriers used in the peptide synthesis for preparing the peptide derivatives of the present invnetion may be conventional ones, and specific examples are polystyrene resins of substituted benzyl type, polystyrene resins of hydroxymethylphenylacetic amide type, substituted benzhydrylpolystyrene resins or polyacrylamide resins having a functional group for binding to a peptide. Amino acids condensation may be also conventional, and dicyclohexylcarbodiimide (DDC), acid anhydride, and activated ester methods may be used. 
     Protective groups in the starting protected amino acids may be groups which are known in conventional peptide synthesis and easily removed by conventional means such as acid decomposition, reduction or aminolysis. Specific examples of amino protective group are formyl; trifluoroacetyl; benzyloxycarbonyl; substituted benzyloxycarbonyls such as (ortho- or para-) chlorobenzyloxycarbonyl, and (ortho- or para-) bromobenzyloxycarbonyl; and aliphatic oxycarbonyl such as t-butoxycarbonyl and t-amyloxycarbonyl. Carboxylic acid in amino acids may be protected by being converted to ester group. As the ester group, there may be mentioned benzyl ester; substituted benzyl ester such as methoxybenzyl ester; alkyl esters such as cyclohexyl ester, cycloheptyl ester, or t-butyl ester. Guanidino group does not require any protective group, but may be protected by nitro; or arylsulfonyl such as tosyl, methoxybenzenesulfonyl, or mesithylenesulfonyl. Protecting groups for imidazole include tosyl, benzyl, and dinitrophenyl. Hydroxy groups present in serine and threonine molecules may be non-protected or protected by benzyl or substituted benzyl. The indole group in tryptophan molecule may be non-protected or protected by formyl or the like. 
     The final deprotection and detachment of a resultant peptide from the carrier may be conducted by the action of anhydrous hydrogen floride in the presence of one of various scavengers. Examples of the scavengers are anisole, (ortho-, metha-, or para-) cresol, dimethylsulfide, thiocresol, ethanediol, and mercaptopyridine, which are all conventional in peptide synthesis. Purification of the resultant peptide may be conducted by means of conventional methods, such as gel-filtration, ion-exchange chromatography, and high- or low-pressure reverse phase chromatography. The peptide thus purified may be converted to its salt by the use of gel-chromatography equilibrated with aqueous acetic acid or aqueous hydrochloric acid. 
    
    
     BEST MODE FOR PRACTICING THE INVENTION 
     The following examples are presented by way of illustration of certain specific embodiments of the invention. The examples are representative only and should not be construed as limiting in any respect. 
     EXAMPLE 1 
     Synthesis of Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-His-Thr-Ala-NH 2   (compound 1 in Table 1) 
     The tile peptide was synthesized by routine solid phase method. As the solid phase carrier, 1% cross-linked 4-methylbenzylhydrylamine polystyrene (amino group content: 0.5 mmol) was used. Amino acid derivatives used for the peptide synthesis were; 
     Box-Ala, Boc-Asp(OcHx), Boc-Asn, Boc-Arg(Tos), Boc-Gly, Boc-Glu(OcHx), Boc-Gln, Boc-His(Tos), Boc-Ile, Boc-Leu, Boc-Lys(Cl-Z), Boc-Met, Boc-Phe, Boc-Ser(Bzl), Boc-Thr(Bzl), Boc-Val 
     The elongation of peptide chain was performed by repeating the steps described in Table 2. 
     
                       TABLE 2                                                     
______________________________________                                    
                    number of  Time                                       
Treatment           repeats    (min)                                      
______________________________________                                    
Deprotection [Treatment 1]                                                
1. washing with dichloromethane                                           
                    1          1.0                                        
2. washing with 50% trifluoroacetic                                       
                    1          5.0                                        
acid/dichloromethane                                                      
3. deprotection with 50% trifluoro-                                       
                    1          25                                         
acetic acid/dichloromethane                                               
4. washing with dichloromethane                                           
                    1          1.0                                        
Neutralization [Treatment 2]                                              
1. 10% diisopropylethylamine                                              
                    2          2.0                                        
/dichloromethane                                                          
2. washing with dichloromethane                                           
                    2          5.0                                        
3. washing with dimethylformamide                                         
                    5          1.0                                        
Condensation* [Treatment 3]                                               
1. symmetric acid anhydride of                                            
                    1          1.0                                        
tert-butoxycarbonylamino acid                                             
(2-equivalents)**/dimetylformamide                                        
2. washing with dimethylformamide                                         
                    5          1.0                                        
3. washing with dichloromethane                                           
                    5          1.0                                        
______________________________________                                    
 
    
     The carrier and protective groups were removed according to known HF method. In detail, protected peptide-polystyrene was incubated in 10% para-cresol, 65% dimetyl sulfide, and 25% anhydrous hydrogen fluoride (20 ml) at 0° C. for 2 hours, and then the reaction mixture was evaporated to remove the solvent under reduced pressure and treated with 5% para-cresol and 95% anhydrous hydrogen fluoride at 0° C. for 1 hour. After evaporation of the reaction mixure under reduced pressure, the residue was washed with ethyl acetate, extracted with 1M acetic acid, and lyophilized to obtain crude peptide. The crude peptide was applied to reverse phase high pressure chromatography, and eluted with linear gradient of water-acetonitrile containing 0.1% trifluoroacetic acid. After lyophilization, the material was applied to CM Toyopearl 650S (1.5×30 cm) in 10 mM ammonium acetate (pH6.0), and separated and purified with linear gradient of 20 mM-1.0M sodium acetate. The fraction containg desired compound was gel filtrated through Sephadex G25 (15×50 cm) preequilibrated with 2% acetic acid, and then lyophilized, and converted to the acetate by gel filtration previously described to obtain the pure title compound. 
     Yield:31 mg 
     Amino acid analysis : Degraded materials obtained by hydrolysis in 5.5M hydrochloric acid at 110° C. for 48 hours were analized in an amino acid analizer. Theoretical values are shown in parenthesis. Correction on degradation of amino acids during the hydrolysis was not done. 
     Asp 1.93(2), Thr 0.96(1), Ser 1.56(2), Glue 4.07(4) Gly 0.94(1), Ala 2.01(2), Met 0.91(1), Ile 3.84(4) Leu 5.19(5), Phe 1.94(2), Lys 0.95(1), His 3.85(4) Arg 3.13(3) 
     Optical ratation [α] 25   D  : -66° (C=0.24, 1M acetic acid) 
     EXAMPLE 2 
     Synthesis of Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-His-Thr-Ala-NH 2  (compound 3 in Table 1). 
     The title peptide was synthesized by the method as described in Example 1. 
     Optical raotation [α] 25   D  :-65° (C=0.1, 1M acetic acid) 
     EXAMPLE 3 
     Synthesis of Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-His-Thr-Ala-NHz (compound 5 in Table 1). 
     The title peptide was synthesized by the method as described in Example 1. 
     Optical ratation [α] 25   D  :-62° (C=0.1, 1M acetic acid) 
     EXAMPLE 4 
     Synthesis of Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-His-Thr-Ala-Glu-Ile-Arg-Ala-NH.sub.2 (compund 7 in Table 1). 
     The title peptide was synthesized by the method as described in Example 1. 
     Optical ratation [α] 25   D  : -95° (C=0.13, 1M acetic acid) 
     EXPERIMENT 
     Determination of PTH antagonism 
     Method 
     PTH antagonism of the peptide derivatives of the invention was determined on the basis of cAMP production using cultured osteoblast MC3T3-El derived from mice. 
     The cultured cells were plated on 12 well multiwellculture plate at a ratio of 1×10 5  cells/well. Using α-modified MEM containing 10% quassifetal bovine serum as a culture medium, the cells were cultured at 37° C. under 95% air-5% CO 2  for 3 days. The medium was exchanged by α-modified MEM containing 1% bovine serum albumin and incubated for 6 hours. The medium was again exchanged by α-modified MEM containing the peptide derivative in various concentrations, 5×10 -9  M hPTH (1-34), 1% bovine serum albumin, and 1 mM isobutyl methylxanthine, and further incubated. 
     After one hour incubation, the medium and the cells were separated. The separated medium was used as a test sample for determination of cAMP without further treatment. The separated cells was treated with 90% n-propyl alcohol to extract cAMP according to Yamaguchi et al method (Journal of Biological Chemistry, Vol.262, 7711-7718, 1987). cAMP determination was conducted using a cAMP-radioimmunoassay kit which is commercially available. Table 3 shows 50% inhibition of cAMP production caused by the peptide derivatives of the invention when the amount of cAMP produced by 5×10 -9  M hPTH (1-34) is defined as 100%. As a control, [Tyr 34  ]-hPTH (3-34)-NH 2  and hPTHrP (3-34)-NH 2 , which are known as a PTH antagonist, were employed. 
     
                       TABLE 3                                                     
______________________________________                                    
Compound No.            IC.sub.50                                         
______________________________________                                    
Compound 1              0.007                                             
Compound 2              0.008                                             
Compound 3              0.015                                             
Compound 4              0.476                                             
[Tyr.sup.34 ]- hpTH (3-34) - NH.sub.2                                     
                        1                                                 
hpTHrp (3-34) - NH.sub.2                                                  
                        0.087                                             
______________________________________                                    
 
    
     Results 
     Table 3 shows that the compounds of the present invention exhibit 50% inhibition at a concentration of 1/140 as compared with that of [Tyr 34  ]-hPTH (3-34)-NH 2 , and at a concentraiton of 1/12 as compared with hPTHrP (3-34)-NH 2 . 
     Industrial utility 
     The peptide derivatives of the present invention have stronger inhibitory activity against hPTH when compared with conventional inhibitors, and therefore, they are expected to be useful for the treatment of various diseases associated with calcium or phosphoric acid metabolism such as hypercalcemia and osteoporosis, or diseases associated with PTH and PTHrP. 
     
         __________________________________________________________________________
SEQUENCE LISTING                                                          
(1) GENERAL INFORMATION:                                                  
(iii) NUMBER OF SEQUENCES: 21                                             
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(A) LENGTH: 25 amino acid residues                                        
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LeuMetHisAsnLeuGlyLy sSerIleGlnAspLeuArgArgArg                            
151015                                                                    
PhePheLeuHisHisLeuIleAlaGluIle                                            
2025                                                                      
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(A) LENGTH: 28 amino acid residues                                        
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 (A) NAME/KEY: modified-site                                              
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(D) OTHER INFORMATION: /note=&#34;Ala-OH or                                   
Ala-NH2&#34;                                                                  
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LeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArgArgArg                             
1510 15                                                                   
PhePheLeuHisHisLeuIleAlaGluIleHisThrXaa                                   
2025                                                                      
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 Ala-NH2&#34;                                                                 
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LeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArgArgArg                             
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PhePheLeuHisHisLeuIleAlaGluIleHisThrAl aGluIle                            
202530                                                                    
ArgXaa                                                                    
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Val-NH2&#34;                                                                  
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LeuMetHisAsn LeuGlyLysSerIleGlnAspLeuArgArgArg                            
151015                                                                    
PhePheLeuHisHisLeuIleAlaGluIleHisThrAlaGluIle                             
2025 30                                                                   
ArgAlaThrSerGluXaa                                                        
35                                                                        
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(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(v iii) POSITION IN GENOME:                                               
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 43                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Asn-OH or                                   
Asn-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
 (B) TITLE:                                                               
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                   
LeuMetHisAsnLeuGlyL ysSerIleGlnAspLeuArgArgArg                            
151015                                                                    
PhePheLeuHisHisLeuIleAlaGluIleHisThrAlaGluIle                             
202530                                                                    
ArgAlaThrSerGluValSerProAsnSerLysProXaa                                   
3540                                                                      
(2) INFORMATION FOR SEQ ID NO:6:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 29 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 29                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ala-OH or                                   
Ala-NH2&#34;                                                                  
 (x) PUBLICATION INFORMATION:                                             
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                  
GlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArgArg                             
151015                                                                    
ArgPhePheLeuHisHisLeuIleAlaGluIleHisThrXaa                                
20 25                                                                     
(2) INFORMATION FOR SEQ ID NO:7:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 33 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
 (B) STRAIN:                                                              
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
 (B) MAP POSITION:                                                        
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 33                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ala-OH or                                   
Ala-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
 (D) VOLUME:                                                              
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                   
GlnLeuMetHisAsnLeuGlyLysSerIleGlnAspL euArgArg                            
151015                                                                    
ArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAlaGlu                             
202530                                                                    
IleArgXaa                                                                 
(2) INFORMATION FOR SEQ ID NO:8:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 37 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
 (D) DEVELOPMENTAL STAGE:                                                 
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
 (C) UNITS:                                                               
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 37                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Val-OH or                                   
Val-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
( E) ISSUE:                                                               
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                   
GlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArgArg                             
1 51015                                                                   
ArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAlaGlu                             
202530                                                                    
IleArgAlaThrSerGluXaa                                                     
35                                                                        
(2) INFORMATION FOR SEQ ID NO:9:                                          
 (i) SEQUENCE CHARACTERISTICS:                                            
(A) LENGTH: 44 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
 (D) DEVELOPMENTAL STAGE:                                                 
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C ) UNITS:                                                               
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 44                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Asn-OH or                                   
Asn-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
(E) ISSUE:                                                                
 (F) PAGES:                                                               
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                   
GlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArgArg                             
15 1015                                                                   
ArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAlaGlu                             
202530                                                                    
IleArgAlaThrSerGluValSerProAsnSerLysPro Xaa                               
3540                                                                      
(2) INFORMATION FOR SEQ ID NO:10:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 30 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
 (A) ORGANISM:                                                            
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
 (A) CHROMOSOME/SEGMENT:                                                  
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 1                                                           
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
Leu&#34;                                                                      
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 30                                                          
 (C) IDENTIFICATION METHOD:                                               
(D) OTHER INFORMATION: /note=&#34;Ala-OH or                                   
Ala-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
 (I) FILING DATE:                                                         
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                  
XaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArg                             
151015                                                                    
ArgArgP hePheLeuHisHisLeuIleAlaGluIleHisThrXaa                            
202530                                                                    
(2) INFORMATION FOR SEQ ID NO:11:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 34 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(i i) MOLECULE TYPE:                                                      
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
( I) ORGANELLE:                                                           
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 1                                                           
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
 Leu&#34;                                                                     
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 34                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ala-OH or                                   
Ala-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
 (E) ISSUE:                                                               
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                  
XaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArg                             
1 51015                                                                   
ArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAla                             
202530                                                                    
GluIleArgXaa                                                              
(2) INFORMATION FOR SEQ ID NO:12:                                         
(i ) SEQUENCE CHARACTERISTICS:                                            
(A) LENGTH: 38 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
( D) DEVELOPMENTAL STAGE:                                                 
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
 (ix) FEATURE:                                                            
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 1                                                           
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
Leu&#34;                                                                      
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 38                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Val-OH or                                   
 Val-NH2&#34;                                                                 
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                  
XaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArg                             
151015                                                                    
ArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAla                             
202530                                                                    
GluIleArgAlaThrSerGluXaa                                                  
35                                                                        
(2) INFORMATION FOR SEQ ID NO:13:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 45 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(i ii) HYPOTHETICAL:                                                      
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vi i) IMMEDIATE SOURCE:                                                  
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 1                                                           
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
 Leu&#34;                                                                     
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 45                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Asn-OH or                                   
Asn-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                  
XaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeuArg                             
1 51015                                                                   
ArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThrAla                             
202530                                                                    
GluIleArgAlaThrSerGluValSerProAsnSerL ysProXaa                            
354045                                                                    
(2) INFORMATION FOR SEQ ID NO:14:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 31 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
 (B) CLONE:                                                               
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 2                                                           
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
Leu&#34;                                                                      
(ix) FEATURE:                                                             
 (A) NAME/KEY: modified-site                                              
(B) LOCATION: 31                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ala-OH or                                   
Ala-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
(E) ISSUE:                                                                
(F) PAGES:                                                                
 (G) DATE:                                                                
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                  
GluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeu                             
1510 15                                                                   
ArgArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThr                             
202530                                                                    
Xaa                                                                       
(2) INFORMATION FOR SEQ ID NO:15:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 35 amino acid residues                                        
(B) TYPE: amino acid                                                      
 (C) STRANDEDNESS: single                                                 
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 2                                                           
 (C) IDENTIFICATION METHOD:                                               
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
Leu&#34;                                                                      
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 35                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ala-OH or                                   
Ala-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
 (C) JOURNAL:                                                             
(D) VOLUME:                                                               
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                  
GluXaaGlnLeuMetHisAsnLeuG lyLysSerIleGlnAspLeu                            
151015                                                                    
ArgArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThr                             
202530                                                                    
AlaG luIleArgXaa                                                          
35                                                                        
(2) INFORMATION FOR SEQ ID NO:16:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 39 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
 (B) STRAIN:                                                              
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A ) CHROMOSOME/SEGMENT:                                                  
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 2                                                           
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
Leu&#34;                                                                      
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 39                                                          
(C ) IDENTIFICATION METHOD:                                               
(D) OTHER INFORMATION: /note=&#34;Val-OH or                                   
Val-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                  
GluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAspLeu                             
151015                                                                    
ArgArgArgPhePhe LeuHisHisLeuIleAlaGluIleHisThr                            
202530                                                                    
AlaGluIleArgAlaThrSerGluXaa                                               
35                                                                        
(2) INFORMATION FOR SEQ ID NO:17:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 46 amino acid residues                                        
(B) TYPE: amino acid                                                      
 (C) STRANDEDNESS: single                                                 
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 2                                                           
 (C) IDENTIFICATION METHOD:                                               
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
Leu&#34;                                                                      
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 46                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Asn-OH or                                   
Asn-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
 (C) JOURNAL:                                                             
(D) VOLUME:                                                               
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                  
GluXaaGlnLeuMetHisAsnLeuG lyLysSerIleGlnAspLeu                            
151015                                                                    
ArgArgArgPhePheLeuHisHisLeuIleAlaGluIleHisThr                             
202530                                                                    
AlaG luIleArgAlaThrSerGluValSerProAsnSerLysPro                            
354045                                                                    
Xaa                                                                       
(2) INFORMATION FOR SEQ ID NO:18:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 32 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
 (I) ORGANELLE:                                                           
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 3                                                           
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
Leu&#34;                                                                      
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 32                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ala-OH or                                   
Ala-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
 (D) VOLUME:                                                              
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                  
SerGluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGln Asp                            
151015                                                                    
LeuArgArgArgPhePheLeuHisHisLeuIleAlaGluIleHis                             
202530                                                                    
ThrXaa                                                                    
(2) INFORMATION FOR SEQ ID NO:19:                                         
 (i) SEQUENCE CHARACTERISTICS:                                            
(A) LENGTH: 36 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
 (D) DEVELOPMENTAL STAGE:                                                 
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
 (ix) FEATURE:                                                            
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 3                                                           
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
Leu&#34;                                                                      
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 36                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ala-OH or                                   
 Ala-NH2&#34;                                                                 
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                  
SerGluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAsp                             
151015                                                                    
LeuArgArgArgPhePheLeuHisHisLeuIleAlaGluIleH is                            
202530                                                                    
ThrAlaGluIleArgXaa                                                        
35                                                                        
(2) INFORMATION FOR SEQ ID NO:20:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 40 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
 (iv) ANTI-SENSE:                                                         
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
 (A) LIBRARY:                                                             
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
(B) MAP POSITION:                                                         
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 3                                                           
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
Leu&#34;                                                                      
 (ix) FEATURE:                                                            
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 40                                                          
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Val-OH or                                   
Val-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
(E) ISSUE:                                                                
 (F) PAGES:                                                               
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
(J) PUBLICATION DATE:                                                     
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                  
SerGluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAsp                             
15 1015                                                                   
LeuArgArgArgPhePheLeuHisHisLeuIleAlaGluIleHis                             
202530                                                                    
ThrAlaGluIleArgAlaThrSerGluXaa                                            
35 40                                                                     
(2) INFORMATION FOR SEQ ID NO:21:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 47 amino acid residues                                        
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS: single                                                  
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE:                                                       
(iii) HYPOTHETICAL:                                                       
(iv) ANTI-SENSE:                                                          
(v) FRAGMENT TYPE:                                                        
(vi) ORIGINAL SOURCE:                                                     
(A) ORGANISM:                                                             
(B) STRAIN:                                                               
(C) INDIVIDUAL ISOLATE:                                                   
(D) DEVELOPMENTAL STAGE:                                                  
(E) HAPLOTYPE:                                                            
(F) TISSUE TYPE:                                                          
(G) CELL TYPE:                                                            
(H) CELL LINE:                                                            
(I) ORGANELLE:                                                            
(vii) IMMEDIATE SOURCE:                                                   
(A) LIBRARY:                                                              
(B) CLONE:                                                                
(viii) POSITION IN GENOME:                                                
(A) CHROMOSOME/SEGMENT:                                                   
 (B) MAP POSITION:                                                        
(C) UNITS:                                                                
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 3                                                           
(C) IDENTIFICATION METHOD:                                                
(D) OTHER INFORMATION: /note=&#34;Ile, Thr, Val or                            
Leu&#34;                                                                      
(ix) FEATURE:                                                             
(A) NAME/KEY: modified-site                                               
(B) LOCATION: 47                                                          
(C) IDENTIFICATION METHOD:                                                
 (D) OTHER INFORMATION: /note=&#34;Asn-OH or                                  
Asn-NH2&#34;                                                                  
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS:                                                              
(B) TITLE:                                                                
(C) JOURNAL:                                                              
(D) VOLUME:                                                               
(E) ISSUE:                                                                
(F) PAGES:                                                                
(G) DATE:                                                                 
(H) DOCUMENT NUMBER:                                                      
(I) FILING DATE:                                                          
 (J) PUBLICATION DATE:                                                    
(K) RELEVANT RESIDUES IN SEQ ID NO:                                       
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                  
SerGluXaaGlnLeuMetHisAsnLeuGlyLysSerIleGlnAsp                             
151015                                                                    
LeuArgArgArgPhePheLeuH isHisLeuIleAlaGluIleHis                            
202530                                                                    
ThrAlaGluIleArgAlaThrSerGluValSerProAsnSerLys                             
354045                                                                    
ProXaa