Patent Publication Number: US-5831002-A

Title: Antitumor peptides

Description:
This application is a continuation-in-part of application Ser. No. 08/431,795, filed May 1, 1995, now abandoned, which is a continuation of application Ser. No. 07/985,696 filed Nov. 25, 1992, now abandoned, which is a continuation-in-part of application Ser. No. 07/885,788 filed May 20, 1992, now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     It is known that peptides isolated from marine origin like Dolastatin-10 (U.S. Pat. No. 4,816,444) and Dolastatin-15 (EP-A-398558) show potent cell growth inhibitory activity (cf.: Biochem. Pharmacology 40, no. 8, 1859-64, 1990); J. Natl. Cancer Inst. 85, 483-88, 1993 and references cited therein). Based upon interesting results in experimental tumor systems in vivo, further preclinical evaluation of these natural products is currently under way in order to initiate clinical studies in cancer patients. However, the natural products have disadvantages, such as poor solubility in aqueous solvents and costly building blocks needed for synthesis. The invention described herein provides novel peptides and derivatives thereof which offer improved therapeutic potential for the treatment of neoplastic diseases as compared to Dolastatin-10 and Dolastatin-15. Furthermore, the compounds of this invention may be conveniently synthesized as described in detail below. 
     DETAILED DESCRIPTION OF THE INVENTION 
     Compounds of this invention include novel peptides of the formula I 
     
         R.sup.1 R.sup.2 N--CHX--CO--A--B--D--(E).sub.s --(F).sub.t --(G).sub.U --KI 
    
     where 
     R 1  is alkoxy, preferably C 1  -C 4  ; alkyl, preferably C 1-7  ; cycloalkyl, preferably C 3-6  ; alkylsulfonyl, preferably C 1-6  ; fluoroalkyl, preferably fluoroethyl, difluoroethyl, fluoroisopropyl, trifluoroisopropyl; aminosulfonyl which may be substituted by alkyl, preferably C 1-5  ; hydroxy; or benzyl which may be substituted by up to three substitutents independently selected from alkyl (preferably C 1-4 ), alkoxy (preferably C 1-4 ), nitro, halogen and CF 3  ; 
     R 2  is hydrogen; alkyl, preferably C 1-4;  fluoroalkyl, preferably fluoroethyl, difluoroethyl, fluoroisopropyl, trifluoroisopropyl; or cycloalkyl, preferably C 3--7  ; 
     R 1  --N-R 2  together may be a 5- or 6-membered heterocycle which may be unsubstituted or substituted with one or more substitutents independently selected from alkyl (preferably C 1-4 ), N(CH 3 ) 2 , nitro, CONH 2  and COOEt; 
     A is a valyl, isoleucyl, leucyl, allo-isoleucyl, 2,2-dimethylglycyl, 2-cyclopropylglycyl, 2-cyclopentylglycyl, 3-tert-butylalanyl, 2-tert-butylglycyl, 3-cyclohexylalanyl, 2-ethylglycyl, 2-cyclohexylglycyl, norleucyl or norvalyl residue; 
     B is a N-alkyl-valyl, -norvalyl, -leucyl, -isoleucyl, -2-tert-butylglycyl, -3-tert-butylalanyl, -2-ethylglycyl, -2-cyclopentylglycyl, -2-cyclopentylglycyl, norleucyl or -2-cyclohexylglycyl residue where N-alkyl is preferably N-methyl or N-ethyl; 
     D is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue; 
     E is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue; 
     F and G are independently selected from the group consisting of prolyl, homoprolyl, hydroxyprolyl, thiazolidinyl-4-carbonyl, 1-aminopentyl -1-carbonyl, valyl, 2-tert-butylglycyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl, N-methylphenylalanyl, tetrahydroisoquinolyl -2-carbonyl, 3-thiazolylalanyl, 3-thienylalanyl, histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylalanyl, 2-cyclohexylglycyl, norleucyl, norvalyl, neopentylglycyl, tryptophanyl, glycyl, alanyl, β-alanyl and 3-naphthylalanyl residues; 
     x is hydrogen, alkyl (preferably C 1-5 ), cycloalkyl (preferablyl C 3-7 ), --CH 2  -cyclohexyl or arylalkyl (preferably benzyl or phenethyl); 
     s, t and u are independently 0 or 1; and 
     K is hydroxy, alkoxy (preferably C 1-4 ), phenoxy, benzyloxy or a substituted or unsubstituted amino moiety; 
     and the salts thereof with physiologically tolerated acids. 
     This invention also provides methods for preparing the compounds of formula I, pharmaceutical compositions containing such compounds together with a pharmaceutically acceptable carrier and methods for using same for treating cancer in mammals. 
     One subclass of compounds of this invention includes compounds of formula I wherein R 1  --N--R 2  is a pyrrolidinyl or piperidinyl residue which may be unsubstituted or substituted with one or more substituents which may independently be selected from alkyl (preferably C 1-4 ), N(CH 3 ) 2 , nitro, oxo, CONH 2  and COOEt; 
     Another subclass of compounds of this invention includes compounds of formula I wherein K is an amino moiety of the formula R 5  --N--R 6  wherein 
     R 5  is hydrogen, or hydroxy, or C 1-7  alkoxy, or benzyloxy (which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, phenoxy, benzoxy, halogen, C 1-4  -alkyl, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or phenyloxy (which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, phenoxy, benzoxy, halogen, C 1-4  -alkyl, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or C 1-12  -alkyl (which may be substituted by one or more fluoro atoms), or C 3-7  -cycloalkyl, or benzyl (which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, phenoxy, benzoxy, halogen, C 1-4  -alkyl, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ); 
     R 6  is hydrogen, or C 1-12  alkyl (which may be substituted by one or more fluoro atoms), or --(CH 2 ) v  ,--C 3-7  -cycloalkyl (v=0,1,2, or 3), or norephedryl, or norpseudoephedryl, or quinolyl, or pyrazyl, or --CH 2  -benzimidazolyl, or adamantyl, or --CH 2  -adamantyl, or alpha-methyl-benzyl, or alpha-dimethylbenzyl, or 
     --(CH 2 ) v ,-phenyl (v=0,1,2,or 3; which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, phenoxy, benzoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or 
     --(CH 2 ) m  -naphthyl (m=0 or 1; which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or 
     --(CH 2 ) w  -benzhydryl (w=0,1, or 2; which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or 
     biphenyl (which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or pyridyl (which may be substituted by up to two substitutents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH 2 ), or picolyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH 2 ), or 
     --CH 2  --CH 2  -pyridyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH 2 ), or benzothiazolyl (which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or benzoisothiazolyl (which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or benzopyrazolyl (which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or benzoxazolyl (which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or 
     --(CH 2 ) m  -fluorenyl (m=0 or 1; which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or pyrimidyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or 
     --(CH 2 ) m ,-indanyl (m=0 or 1; which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C1-4-alkyl which may form a cyclic system, cyano, hydroxy, N(CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 ), or 
     --(CH 2  CH 2  O) y  --CH 3  (y=0,1,2,3,4, or 5), or 
     --(CH 2  CH 2  O) y  --CH 2  CH 3  (y=0,1,2,3,4, or 5), or 
     --NH--C 6  H 5  (which may be substituted by up to two substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH 2 ), or 
     --NCH 3  --C 6  H 5  (which may be substituted by up to two substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH 2 ), or 
     --NH--CH 2  --C 6  H 5  (which may be substituted by up to two substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH 2 ), or 
     --NCH 3  --CH 2  --C 6  H 5  (which may be substituted by up to two substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, halogen, C 1-4  -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH 2 ), or 
     5-membered heteroaryl which may be substituted by up to three substituents which may independently be CF 3 , nitro, C 1-7  alkylsulfonyl, C 1-4  alkoxy, thiomethyl, thioethyl, picolyl, acetyl, C 3-6  -cycloalkyl, thiophenyl, --CH 2  --COOEt, C 3-4  -alkylen group forming a bicyclic system with the heterocycle, phenyl (which may be substituted by up to three substituents which may independently be nitro, CF 3 , CN, halogen, or C 1-4  -alkyl), benzyl (which may be substituted by up to three substituents which may independently be nitro, CF 3 , halogen, C 1-4  -alkyl, C 1-7  -alkylsulfonyl, cyano, hydroxy, C 1-4  -dialkylamino), or 
     --CHR 7  -5-membered heteroaryl (which may be substituted by up to two subsituents which may independently be CF 3 , nitro, cyano, halogen, COOMe, COOEt, COOiPr, CONH 2 , C 1-4  -alkyl, C 1-4  -alkoxy, phenyl, benzyl, naphthyl, or C 1-7  -alkylsulfonyl  R 7  =hydrogen, linear or branched C 1-5  alkyl, benzyl; or R 7  and R 5  together form a group --(CH 2 ) 3  --or --(CH 2 ) 4  --!). 
     This subclass includes compounds of formula I wherein s, t and u are independently 0 or 1; R 1 , R 2  and X are lower alkyl, A is a lower alkyl amino acid, B is a N-loweralkylated lower alkyl amino acid; D,E,F,G and K are as previously defined. With the foregoing in mind, three sets of such compounds can thus be depicted by the following formulas II, III, and IV: 
     
         R.sup.1 R.sup.2 N-CXH-CO-A-B-Pro-Pro-F-G-K                 II 
    
     
         R.sup.1 R.sup.2 N-CXH-CO-A-B-Pro-Pro-F-K                   III 
    
     
         R.sup.1 R.sup.2 N-CXH-CO-A-B-Pro-Pro-K                     IV 
    
     --CHR 7  -5-membered heteroaryl may for example be represented by one of the following residues: ##STR1## --NR 5  CHR 7  --5-membered heteroaryl may for example be represented by the following residues: ##STR2## 5-membered heteroaryl may for example be represented by the following residues: ##STR3## 
     In another subclass of compounds of this invention R 5  --N--R 6  together may form structures selected from the group consisting of ##STR4## which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of CF 3 , nitro, halogen, oxo, cyano, formyl, N,N-dimethylamino, C 1-6  -alkyl, C 3-6  -cycloalkyl, C 3-4  -alkylen group forming a bicyclic system with the heterocycle, C 1-4  -alkoxy, phenoxy, benzoxy, naphthyl, pyrimidyl, COOEt, pyrrolidinyl, piperidinyl, thienyl, pyrrolyl, CH 2  --CO--NCH(CH 3 ) 2 , --CH 2  --CO--N(CH 2 ) 4 , --CH 2  --CO--N(CH2) 4  0, benzyl (which may be substituted by up to three substituents independently selected from the group consisting of nitro, halogen, CF 3 , thiomethyl or the corresponding sulfoxide or sulfone, thioethyl or the corresponding sulfoxide or sulfone, C 1-4  -alkyl, and C 1-4  -alkoxy). 
     Still another subclass of compounds of this invention includes for example compounds of formula I wherein s, t and u are 1 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety. 
     Yet another subclass of compounds of this invention includes for example compounds of formula I wherein s and t are 1, u is 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety. 
     Another subclass of compounds of this invention includes for example compounds of formula I wherein s is 1, t and u are 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety. 
     These examples illustrate but do not limit the scope of the present invention. 
     The peptides of the formula I are composed preferably of L-amino acids but they may contain one or more D-amino acids. 
     The new compounds may be present as salts with physiologically tolerated acids such as: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine. 
     The novel compounds can be prepared by known methods of peptide chemistry. Thus, the peptides can be assembled sequentially from amino acids or by linking suitable small peptide fragments. In the sequential assemblage, starting at the C terminus the peptide chain is extended stepwise by one amino acid each time. In fragment coupling it is possible to link together fragments of different lengths, and the fragments in turn can be obtained by sequential assemblage from amino acids or themselves by fragment coupling. 
     Both in the sequential assemblage and in the fragment coupling it is necessary to link the units by forming an amide linkage. Enzymatic and chemical methods are suitable for this. 
     Chemical methods for forming the amide linkage are described in detail by Mueller, Methoden der organischen Chemie Vol. XV/2, pp 1 to 364, Thieme Verlag, Stuttgart, 1974; Stewart, Young, Solid Phase Peptide Synthesis, pp 31 to 34, 71 to 82, Pierce Chemical Company, Rockford, 1984; Bodanszky, Klausner, Ondetti, Peptide Synthesis, pp 85 to 128, John Wiley &amp; Sons, New York, 1976 and other standard works on peptide chemistry. Particular preference is given to the azide method, the symmetric and mixed anhydride method, in situ generated or preformed active esters, the use of urethane protected N-carboxy anhydrides of amino acids and the formation of the amide linkage using coupling reagents (activators, especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC ), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propanephosphonic anhydride (PPA), N,N-bis(2-oxo-3-oxazolldinyl)-amidophosphoryl chloride (BOP-Cl), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop), diphenylphosphoryl azide (DPPA), Castro&#39;s reagent (BOP, PyBop), 0-benzotriazolyl-N,N,N&#39;, N&#39;-tetramethyluronium salts (HBTU), diethylphosphoryl cyanide (DEPCN), 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene dioxide (Steglich&#39;s reagent; HOTDO) and 1,1&#39;-carbonyldiimidazole (CDI). The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), Azabenzotriazole, N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine. 
     Whereas it is normally possible to dispense with protective groups in enzymatic peptide synthesis, reversible protection of reactive groups not involved in formation of the amide linkage is necessary for both reactants in chemical synthesis. Three conventional protective group techniques are preferred for the chemical peptide synthesis: the benzyloxycarbonyl (Z), the t-butoxycarbonyl (Boc) and the 9-fluorenylmethoxycarbonyl (Fmoc) techniques. Identified in each case is the protective group on the alpha-amino group of the chain-extending unit. A detailed review of amino-acid protective groups is given by Mueller, Methoden der organischen Chemie Vol. XV/1, pp 20 to 906, Thieme Verlag, Stuttgart, 1974. The units employed for assembling the peptide chain can be reacted in solution, in suspension or by a method similar to that described by Merrifield in J. Amer. Chem. Soc. 85 (1963) 2149. Particularly preferred methods are those in which peptides are assembled sequentially or by fragment coupling using the Z, Boc or Fmoc protective group technique, with one of the reactants in the said Merrifield technique being bonded to an insoluble polymeric support (also called resin hereinafter). This typically entails the peptide being assembled sequentially on the polymeric support using the Boc or Fmoc protective group technique, the growing peptide chain being covalently bonded at the C terminus to the insoluble resin particles (cf. FIG. 1 and 2). This procedure makes it possible to remove reagents and byproducts by filtration, and thus recrystallization of intermediates is unnecessary. 
     The protected amino acids can be linked to any suitable polymers, which merely have to be insoluble in the solvents used and to have a stable physical form which makes filtration easy. The polymer must contain a functional group to which the first protected amino acid can be firmly attached by a covalent bond. Suitable for this purpose are a wide variety of polymers, eg. cellulose, polyvinyl alcohol, polymethacrylate, sulfonated polystyrene, chloromethylated styrene/divinylbenzene copolymer (Merrifield resin), 4-methylbenzhydrylamine resin (MBHA-resin), phenylacetamidomethyl-resin (Pam-resin), p-benzyloxy-benzyl-alcohol-resin, benzhydryl-amine-resin (BHA-resin), 4-(hydroxymethyl)-benzoyloxy-methyl-resin, the resin of Breipohl et al. (Tetrahedron Letters 28 (1987) 565; supplied by BACHEM), 4-(2,4-di-methoxyphenylaminomethyl)phenoxy-resin (supplied by Novabiochem) or o-chlorotrityl-resin (supplied by Biohellas). 
     Suitable for peptide synthesis in solution are all solvents which are inert under the reaction conditions, especially water, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) and mixtures of the said solvents. Peptide synthesis on the polymeric support can be carried out in all inert organic solvents in which the amino-acid derivatives used are soluble. However, preferred solvents additionally have resin-swelling properties, such as DMF, DCM, NMP, acetonitrile and DMSO, and mixtures of these solvents. After synthesis is complete, the peptide is cleaved off the polymeric support. The conditions under which cleavage off the various resin types is possible are disclosed in the literature. The cleavage reactions most commonly used are acid- and palladium-catalyzed, especially cleavage in liquid anhydrous hydrogen fluoride, in anhydrous trifluormoethanesulfonic acid, in dilute or concentrated trifluoroacetic acid, palladium-catalyzed cleavage in THF or THF-DCM mixtures in the presence of a weak base such as morpholine or cleavage in acetic acid/dichloromethane/trifluoroethanol mixtures. Depending on the chosen protective groups, these may be retained or likewise cleaved off under the cleavage conditions. Partial deprotection of the peptide may also be worthwhile when certain derivatization reactions are to be carried out. Peptides dialkylated at the N-terminus can be prepared either by coupling on the appropriate N,N-di-alkylamino acids in solution or on the polymeric support or by reductive alkylation of the resin-bound peptide in DMF/1% acetic acid with NaCNBH 3  and the appropriate aldehydes. The various non-naturally occurring amino acids as well as the various non-amino acid moieties disclosed herein may be obtained from commercial sources or synthesized from commercially-available materials using methods known in the art. For example, amino acids building blocks with R 1  and R 2  moieties can be prepared according to E. Wuensch, Houben Weyl, Meth. d. Org. Chemie, Bd. XV, 1, p. 306 following, Thieme Verlag Stuttgart 1974 and Literature cited therein. Peptides with gamma- or delta-lactam bridges can be prepared by incorporating the appropriate lactam-bridged dipeptide units (R. Freidinger, J. Org. Chem. (1982) 104-109) into the peptide chain. Peptides with thiazole-, oxazol-, thiazolin- or oxazolin-containing dipeptide building blocks can be prepared by incorporating the appropriate dipeptidic units (P. Jouin et al., Tetrahedron Letters (1992), 2807-2810; P. Wipf et al., Tetrahedron Letters (1992), 907-910; W.R. Tully, J. Med. Chem. (1991), 2065; Synthesis (1987), 235) into the peptide chain. 
     The compounds of this invention may be used to inhibit or otherwise treat solid tumors (e.g. tumors of the lung, breast, colon, prostate, bladder, rectum, or endometrial tumors) or hematological malignancies (e.g. leukemias, lymphomas) by administration of the compound to the mammal. Administration may be by any of the means which are conventional for pharmaceutical, preferably oncological, agents, including oral and parenteral means such as subcutaneously, intravenously, intramuscularly and intraperitoneally. The compounds may be administered alone or in the form of pharmaceutical compositions containing a compound of formula I together with a pharmaceutically accepted carrier appropriate for the desired route of administration. Such pharmaceutical compositions may be combination products, i.e., may also contain other therapeutically active ingredients. 
     The dosage to be administered to the mammal will contain an effective tumor-inhibiting amount of active ingredient which will depend upon conventional factors including the biological activity of the particular compound employed; the means of administration; the age, health and body weight of the recipient; the nature and extent of the symptoms; the frequency of treatment; the administration of other therapies; and the effect desired. A typical daily dose will be about 0.05 to 100 milligrams per kilogram of body weight, preferably 0.1 to 10 milligrams, on oral administration and about 0.01 to 100 milligrams per kilogram of body weight, preferably 0.05 to 50 milligrams, on parenteral administration. 
     The novel compounds can be administered in conventional solid or liquid pharmaceutical administration forms, e.g. uncoated or (film-)coated tablets, capsules, powders, granules, suppositories or solutions. These are produced in a conventional manner. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release compositions, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme- Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain 1-90% by weight of the active substance. 
     The following examples are intended to illustrate the invention. The proteinogenous amino acids are abbreviated in the examples using the known three-letter code. Other meanings are: TFA=trifluoroacetic acid, Ac=acetic acid, Bu=butyl, Et=ethyl, Me=methyl, Bzl=benzyl, Nal=3-naphthylalanine, Cha=3-cyclohexylalanine, Npg=neopentylglycine, Abu=2-amino butyryl, Dab=2,4-diaminobutyryl. iPr=isopropyl. 
     A. General procedures 
     I. The peptides claimed in claim 1 are either synthesized by classical solution synthesis using standard Z- and Boc-methodology as described above or by standard methods of solid-phase synthesis on a completely automatic model 431A synthesizer supplied by APPLIED BIOSYSTEMS. The apparatus uses different synthetic cycles for the Boc and Fmoc protective group techniques. 
     
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a) Synthetic cycle for the Boc protective group technique                 
______________________________________                                    
1.    30% trifluoroacetic acid in DCM                                     
                             1 × 3 min                              
2.    50% trifluoroacetic acid in DCM                                     
                             1 × 1 min                              
3.    DCM washing            5 × 1 min                              
4.    5% diisopropylethylamine in DCM                                     
                             1 × 1 min                              
5.    5% diisopropylethylamine in NMP                                     
                             1 × 1 min                              
6.    NMP washing            5 × 1 min                              
7.    Addition of preactivated protected                                  
      amino acid (DCC and 1 equivalent of                                 
      HOBt in NMP/DCM);                                                   
      Peptide coupling (1st part)                                         
                             1 × 30 min                             
8.    Addition of DMSO to the reaction                                    
      mixture until it contains 20% DMSO                                  
      by volume                                                           
      Peptide coupling (2nd part)                                         
                             1 × 16 min                             
9.    Addition of 3.8 equivalents of                                      
      diisopropylethylamine to the reaction                               
      mixture                                                             
      Peptide coupling (3rd part)                                         
                             1 × 7 min                              
10.   DCM washing            3 × 1 min                              
11.   if conversion is incomplete,                                        
      repetition of coupling (back to 6.)                                 
12.   10% acetic anhydride,                                               
      5% diisopropylethylamine in DCM                                     
                             1 × 2 min                              
13.   10% acetic anhydride in DCM                                         
                             1 × 4 min                              
14.   DCM washing            4 × 1 min                              
15.   back to 1.                                                          
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     BOP-Cl and PyBrop were used as reagents for coupling of the amino acid following N-methylamino acids. The reaction times were correspondingly increased. In solution synthesis, the use of either Boc-protected amino acid NCAs (N-tert.-butyloxycarbonyl-amino acid-N-carboxy-anhydrides) or Z-protected amino acid NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides) respectively is most advantageous for this type of coupling. 
     
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b) Synthetic cycle for the Fmoc protective group technique                
______________________________________                                    
1.     DMF washing          1 × 1 min                               
2.     20% piperidine in DMF                                              
                            1 × 4 min                               
3.     20% piperidine in DMF                                              
                            1 × 16 min                              
4.     DMF washing          5 × 1 min                               
5.     Addition of the preactivated                                       
       protected amino acid (activation                                   
       by 1 equivalent of TBTU and                                        
       5 equivalents of DIPEA in DMF);                                    
       Peptide coupling     1 × 61 min                              
6.     DMF washing          3 × 1 min                               
7.     if conversion is incomplete,                                       
       repetition of coupling (back to 5.)                                
8.     10% acetic anhydride in DMF                                        
                            1 × 8 min                               
9.     DMF washing          3 × 1 min                               
10.    back to 2.                                                         
______________________________________                                    
 
    
     BOP-Cl and PyBrop were used as reagents for coupling on the amino acid following the N-methylamino acids. The reaction times were correspondingly increased. 
     II. Reductive alkylation of the N terminus 
     The peptide-resin prepared as in AIa or AIb was deprotected at the N terminus (steps 2-4 in AIb or 1-6 in AIa) and then reacted with a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acid with addition of 3 equivalents of NaCNBH 3 . After reaction was complete (negative Kaiser test) the resin was washed several times with water, isopropanol, DMF and dichloromethane. 
     III. Workup of the peptide-resins obtained as in Ia and II 
     The peptide-resin was dried under reduced pressure and transferred into a reaction vessel of a TEFLON HF apparatus (supplied by PENINSULA). Addition of a scavenger, preferably anisole (1 ml/g of resin), and in the case of tryptophan-containing peptides of a thiol to remove the indolic formyl group, preferably ethanedithiol (0.5 ml/g of resin), was followed by condensing in hydrogen fluoride (10 ml/g of resin) while cooling with liquid N 2 . The mixture was left to warm to 0° C. and stirred at this temperature for 45 min. The hydrogen fluoride was then stripped off under reduced pressure, and the residue was washed with ethyl acetate in order to remove remaining scavenger. The peptide was extracted with 30% acetic acid and filtered, and the filtrate was lyophilized. 
     IV. Work-up of the peptide-resins obtained as in Ib and II 
     The peptide-resin was dried under reduced pressure and then subjected to one of the following cleavage procedures, depending on the amino-acid composition (Wade, Tregear, Howard Florey Fmoc Workshop Manual, Melbourne 1985). 
     Cleavage conditions: 
     
         ______________________________________                                    
TFA          Scavenger  Reaction time                                     
______________________________________                                    
1.     95%       5% water   1.5 h                                         
2.     95%       5% ethanethiol/                                          
                            1.5 h                                         
                 anisol (1:3)                                             
______________________________________                                    
 
    
     The suspension of the peptide-resin in the suitable TFA mixture was stirred at room temperature for the stated time and then the resin was filtered off and washed with TFA and DCM. The filtrate and the washings were concentrated, and the peptide was precipitated by addition of diethyl ether. After cooling in an ice bath, the precipitate was filtered off, taken up in 30% acetic acid and lyophilized. 
     V. When an o-chlorotrityl-resin (supplied by Biohellas) is used, the suspension of the peptide-resin in an acetic acid/trifluoroethanol/dichloromethane mixture (1:1:3) is stirred at room temperature for 1 h. The resin is then filtered off with suction and thoroughly washed with the cleavage solution. The combined filtrates are concentrated in acuo and treated with water. The precipitated solid is removed by filtration or centrifugation, washed with diethyl ether and dried under reduced pressure. 
     VI. Purification and characterization of the peptides 
     Purification was carried out by gel chromatography (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH) with or without subsequent medium pressure chromatography (stationary phase: HD-SIL C-18, 20-45 mikron, 100 Angstrom; mobile phase: gradient with A=0.1% TFA/ MeOH, B=0.1% TFA/water). 
     The purity of the resulting products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 5 l, 300 A; mobile phase: acetonitrile-water gradient, buffered with 0.1% TFA, 40° C.). 
     Characterization was by amino-acid analysis and fast atom bombardment mass spectroscopy. 
     B. Specific procedures 
    
    
     EXAMPLE 1 
     (SEQ ID NO: 1) 
     N,N-Dimethyl-Val-Val-N-methyl-Val-Pro-Pro-Val-Phe-NH 2   
     1.98 g of Fmoc-RINK-resin (substitution 0.46 mmol/g), corresponding to a batch size of 0.84 mmol, were reacted as in AIb with 1.26 mmol each of 
     Fmoc-Phe-OH 
     Fmoc-Val-OH 
     Fmoc-Pro-OH 
     Fmoc-Pro-OH 
     Fmoc-N-methyl-Val-OH 
     Fmoc-Val-OH 
     Fmoc-Val-OH 
     The amino acid following the N-methylamino acid was coupled on with PyBrop as coupling reagent. After the iterative synthetic cycles were completed, the peptide-resin underwent N-terminal deprotection (steps 2-4 in AIb), and was further reacted with aqueous formaldehyde solution as in AII and then dried under reduced pressure. The resulting resin was subjected to TFA cleavage as in AIV. The crude product (590 mg) was purified by gel filtration (SEPHADEX-LH-20). The yield was 295 mg. 
     EXAMPLE 1 can also be prepared via classical solution phase methodology. The synthesis of N,N-Dimethyl-Val-Val-N-Methyl-Val-Pro-Pro-Val-Phe-NH 2  and its various intermediates is described in the following paragraph. 
     a) Z-MeVal-Pro-OMe 
     66.25 g (250 mmol) Z-MeVal-OH were dissolved in 250 ml dry dichloromethane. After addition of 36.41 ml (262.5 mmol) triethylamine , the reaction mixture was cooled to -25° C. and 32.27 ml (262.5 mmol) pivaloyl chloride were added. 
     After stirring for 2,5 h, 41.89 g (250 mmol) H-Pro-OMe×HCl in 250 ml dichloromethane, neutralized with 36.41 ml (262.5 mmol) triethylamine at 0° C., were added to the reaction mixture. Stirring continued for 2 h at -25° C. and overnight at room temperature. The reaction mixture was diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO 3  solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue (91.24 g) was stirred with petroleum ether overnight and filtered. 62.3 g of product were obtained. 
     b) H-MeVal-Pro-OMe 
     48.9 g (130 mmol) Z-MeVal-Pro-OMe were dissolved in 490 ml methanol. After addition of 10.9 ml (130 mmol) concentrated hydrochloric acid and 2.43 g 10 % Palladium/charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 36.43 g of the product. 
     c) Z-Val-MeVal-Pro-OMe 
     18.1 g (65 mmol) H-MeVal-Pro-OMe, 21.6 g (78 mmol) Z-Val-N-carboxyanhydride and 22.8 ml (130 mmol) diisopropylethylamine were stirred in 110 ml DMF at 40° C. for 2 d. After evaporation of DMF, dichloromethane was added and the organic phase washed with saturated aqueous NaHCO 3  solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate and evaporated to dryness. The product (29.3 g) was obtained as a viscous oil. 
     d) H-Val-MeVal-Pro-OMe 
     29.3 g (61.6 mmol) of Z-Val-MeVal-Pro-OMe were dissolved in 230 ml methanol. After addition of 1.15 g 10% Palladium/charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 21.96 g of the product. 
     e) Z-Val-Val-MeVal-Pro-OMe 
     15.29 g (61 mmol) Z-Val-OH and 21.96 g (61 mmol) H-Val-MeVal-Pro-OMe were dissolved in 610 ml dichloromethane and cooled to 0° C. After addition of 8.16 ml (73.2 mmol) N-Methylmorpholine, 2.77 g (20.3 mmol) HOBt and 11.74 g (61 mmol) EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO 3  solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate and evaporated to dryness to yield 31.96 g of the product. 
     f) Z-Val-Val-MeVal-Pro-OH 
     31.96 g (57 mmol) Z-Val-Val-MeVal-Pro-OMe were dissolved in 250 ml methanol. 102.6 ml of a 1 N LiOH solution was added and the mixture stirred overnight at room temperature. After addition of 500 ml water, the aqueous phase was washed three times with ethyl acetate, adjusted to pH 2 at 0° C. and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness yielding 30.62 g of the desired product as a white solid. 
     g) Z-Val-Val-MeVal-Pro-Pro-Val-Phe-NH 2   
     25 g (43.3 mmol) Z-Val-Val-MeVal-Pro-OH and 15.59 g (43.3 mmol) H-Pro-Val-Phe-NH 2  were suspended in 430 ml of dry dichloromethane. After cooling to 0° C., 5.81 ml (52 mmol) N-methylmorpholine, 1.97 g (15 mmol) HOBt and 8.33 g (43.3 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. The solvents were evaporated, the residue dissolved in 640 ml dichloromethane and thoroughly washed with saturated aqueous NaHCO 3  solution (4×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate and evaporated to dryness to yield 33.04 g of the product. The crude product was chromatographed on a silica gel column with 20% MeOH/Hexane. 18.32 g of the desired product were obtained. 
     h) N,N-Dimethyl-Val-Val-MeVal-Pro-Pro-Val-Phe-NH 2   
     18.32 g Z-Val-Val-MeVal-Pro-Pro-Val-Phe-NH 2  were dissolved in 80 ml methanol. 0.4 g 10% Pd/C were added under nitrogen atmosphere and the reaction mixture hydrogenated at room temperature for 4 h. After addition of 6.22 ml (81.24 mmol) of a 37% aqueous formaldehyde solution, hydrogenation was continued for 5 h. Filtration and evaporation of the solvent gave rise to 15.6 g of crude product. Further purification was achieved by dissolving the peptide in water, adjusting the pH to 2 and extracting the aqueous phase three times with ethyl acetate. The aqueous phase was then adjusted to pH 8-9 and extracted four times with ethyl acetate. The organic phase was washed with water and dried over sodium sulfate to yield 11.3 g of purified product as a white powder. The compound was characterized by fast atom bombardment mass spectrometry ( M+H! +  =797). 
     EXAMPLE 2 
     (SEQ ID NO: 2) 
     N,N-Dimethyl-Val-Val-N-Me-Val-Pro-{1- thiazol-(2)-yl!-2-phenyl}-ethylamide 
     4.11 g of Fmoc-Pro-p-alkoxybenzyl-alcohol-resin (substitution 0.73 mmol/g), corresponding to a batch size of 3 mmol, were reacted as in AIb with 4.5 mmol each of 
     Fmoc-N-MeVal-OH 
     Fmoc-Val-OH 
     Fmoc-Val-OH. 
     The amino acid following the N-methylamino acid was in this case reacted with double coupling using PyBrop or Bop-Cl with increased reaction times. After the synthesis was complete, the peptide-resin underwent N-terminal deprotection (steps 2-4 in AIb), and was further reacted with aqueous formaldehyde solution as in AII and then dried under reduced pressure. The resin obtained in this way was subjected to TFA cleavage as in AIV. The crude product (750 mg) was employed directly for the next coupling. 100 mg of this compound were reacted with 45 mg of (S)-2- l-amino-2-phenylethyl! thiazole and 230 mg of PyBop with the addition of 192 mikroL of DIPEA in DMF at room temperature for 2 d. The reaction mixture was purified by gel chromatography (Sephadex LH-20, methanol) and the product fractions were combined. 83 mg of product were obtained. 
     The following compounds were prepared and can be prepared according to examples 1 and 2: 
     3. Xaa Val Xan Pro Pro Val Phe 
     4. Xaa Val Xan Pro Pro Val Xac 
     5. Xaa Val Xan Pro Pro Val Xad 
     6. Xaa Val Xan Pro Pro Val Xae 
     7. Xaa Val Xan Pro Pro Val Xaf 
     8. Xaa Val Xan Pro Pro Val His NH 2   
     9. Xbo Val Xan Pro Pro Val Phe NH 2   
     10. Xaa Val Xan Pro Pro Val Xag NH 2   
     11. Xaa Val Xan Pro Pro Val Xah 
     12. Xaa Xbe Xan Pro Pro Val Trp NH 2   
     13. Xaa Val Xan Pro Pro Xai Phe NH 2   
     14. Xae Val Xan Pro Pro Ile Phe NH 2   
     15. Xaa Val Xan Pro Xal Val Phe NH 2   
     16. Xaa Val Xan Pro Xak Val Phe NH 2   
     17. Xaa Val Xan Xak Pro Val Phe NH 2   
     18. Xaa Val Xan Xal Pro Val Phe NH 2   
     19. Xaa Val Xao Pro Pro Val Phe NH 2   
     20. Xaa Val Xam Pro Pro Val Phe NH 2   
     21. Xaa Xap Pro Pro Val Phe NH 2   
     22. Xaa Xaq Pro Pro Val Phe NH 2   
     23. Xaa Ile Xan Pro Pro Val Phe NH 2   
     24. Xaa Xai Xan Pro Pro Val Phe NH 2   
     25. Xaa Leu Xan Pro Pro Val Phe NH 2   
     26. Xar Val Xan Pro Pro Val Phe NH 2   
     27. Xas Val Xan Pro Pro Val Phe NH 2   
     28. Xat Val Xan Pro Pro Val Phe NH 2   
     29. Xau Val Xan Pro Xal Val Phe NH 2   
     30. Xav Val Xan Pro Pro Val Phe NH 2   
     31. Xan Val Xan Pro Pro Val Phe NH 2   
     32. Xaw Val Xan Pro Pro Val Phe NH 2   
     33. Xax Vai Xan Pro Pro Val Phe NH 2   
     34. Xaa Val Xan Pro Pro Phe Phe NH 2   
     35. Xaz Val Xan Pro Pro Val Phe NH 2   
     36. Xba Val Xan Pro Pro Val Phe NH 2   
     37. Xaa Val Xan Pro Pro Val NH 2   
     38. Xaa Val Xan Pro Xbb 
     39. Xaa Val Xan Pro Xbc 
     40. Xaa Val Xan Pro Pro Xbd 
     41. Xax Val Xan Pro Pro Val NH 2   
     42. Xaw Val Xan Pro Pro Val NH 2   
     43. Xat Val Xan Pro Pro Val NH 2   
     44. Xaa Xai Xan Pro Pro Val NH 2   
     45. Xaa Val Xan Pro Pro Xal NH 2   
     46. Xaa Val Xan Xak Pro Val NH 2   
     47. Xaa Val Xan Pro Xak Val NH 2   
     48. Xaa Val Xan Pro Pro Val 
     49. Xav Val Xan Pro Pro Val NH 2   
     50. Xaa Val Xan Pro Pro NH 2   
     51. Xaa Val Xan Pro Pro 
     52. Xaa Val Xan Pro Xbf 
     53. Xaa Val Xan Xbb 
     54. Xaa Val Xan Xbc 
     55. Xaa Val Xan Xbg 
     56. Xaa Val Xan Xbh 
     57. Xaa Val Xan Xbi 
     58. Xaa Val Xan Xbk 
     59. Xaa Val Xan Xbl 
     60. Xaa Val Xan Xbm 
     61. Xaa Val Xan Xbn 
     62. Xax Val Xan Pro Pro NH 2   
     63. Xaw Val Xan Pro Pro NH 2   
     64. Xbo Val Xan Pro Pro NH 2   
     65. Xat Val Xan Pro Pro NH 2   
     66. Xaa Xai Xan Pro Pro NH 2   
     67. Xat Xai Xan Pro Pro NH 2   
     68. Xaa Xap Pro Pro NH 2   
     69. Xaa Xaq Pro Pro NH 2   
     70. Xav Val Xan Pro Pro NH 2   
     71. Xaa Xap Pro NH 2   
     72. Xaa Xaq Pro NH 2   
     73. Xaa Val Xan Pro 
     74. Xaa Val Xbp 
     75. Xaa Val Xbq 
     76. Xaa Val Xbr 
     77. Xaa Val Xbs 
     78. Xaa Val Xan Xbf 
     79. Xaa Val Xbt 
     80. Xaa Val Xbu 
     81. Xaa Val Xbv 
     82. Xaa Val Xbw 
     83. Xax Val Xan Pro NH 2   
     84. Xbo Val Xan Pro NH 2   
     85. Xav Val Xan Pro NH 2   
     86. Xaa Val Xan Pro Xbn 
     87. Xaa Val Xan Pro Xbg 
     88. Xaa Val Xan Pro Xbi 
     89. Xaa Val Xan Pro Xbl 
     90. Xbo Val Xan Pro Xbg 
     91. Xbo Val Xan Pro Xbl 
     92. Xbo Xbe Xan Pro Xbg 
     93. Xaa Val Xan Pro Xbx 
     94. Xaa Xbe Xan Pro Pro NH 2   
     95. Xby Val Xan Pro Pro Val Phe NH 2   
     96. Xed Val Xan Pro Pro Val Phe NH 2   
     97. Xee Val Xan Pro Pro Val Phe NH 2   
     98. Xef Val Xan Pro Pro Val Phe NH 2   
     99. Xbz Val Xan Pro Pro Val Phe NH 2   
     100. Xeg Val Xan Pro Pro Val Phe NH 2   
     101. Xca Val Xan Pro Pro Val Phe NH 2   
     102. Xcb Val Xan Pro Pro Val Phe NH 2   
     103. Xcb Val Xao Pro Pro Val Phe NH 2   
     104. Xcc Val Xan Pro Pro Val Phe NH 2   
     105. Xce Val Xan Pro Pro Val Phe NH 2   
     107. Xcg Val Xan Pro Pro Val Phe NH 2   
     108. Xch Val Xan Pro Pro Val Phe NH 2   
     109. Xci Val Xan Pro Pro Val Phe NH 2   
     110. Xck Val Xan Pro Pro Val Phe NH 2   
     111. Xcl Val Xan Pro Pro Val Phe NH 2   
     112. Xcm Val Xan Pro Pro Val Phe NH 2   
     113. Xcn Val Xan Pro Pro Val Phe NH 2   
     114. Xhn Val Xan Pro Pro Val Phe NH 2   
     115. Xho Val Xan Pro Pro Val Phe NH 2   
     116. Xhp Val Xan Pro Pro Val Phe NH 2   
     117. Xhq Val Xan Pro Pro Val Phe NH 2   
     118. Xby Val Xan Pro Pro Val NH 2   
     119. Xed Val Xan Pro Pro Val NH 2   
     120. Xee Val Xan Pro Pro Val NH 2   
     121. Xef Val Xan Pro Pro Val NH 2   
     122. Xbz Val Xan Pro Pro Val NH 2   
     123. Xeg Val Xan Pro Pro Val NH 2   
     124. Xca Val Xan Pro Pro Val NH 2   
     125. Xcb Val Xan Pro Pro Val NH 2   
     126. Xcc Val Xan Pro Pro Val NH 2   
     127. Xce Val Xan Pro Pro Val NH 2   
     128. Xcs Val Xan Pro Pro Val NH 2   
     129. Xch Val Xan Pro Pro Val NH 2   
     130. Xci Val Xan Pro Pro Val NH 2   
     131. Xck Val Xan Pro Pro Val NH 2   
     132. Xcl Val Xan Pro Pro Val NH 2   
     133. Xcm Val Xan Pro Pro Val NH 2   
     134. Xcn Val Xan Pro Pro Val NH 2   
     135. Xhn Val Xan Pro Pro Val NH 2   
     136. Xho Val Xan Pro Pro Val NH 2   
     137. Xhp Val Xan Pro Pro Val NH 2   
     138. Xhq Val Xan Pro Pro Val NH 2   
     139. Xby Val Xan Pro Pro NH 2   
     140. Xed Val Xan Pro Pro NH 2   
     141. Xee Val Xan Pro Pro NH 2   
     142. Xef Val Xan Pro Pro NH 2   
     143. Xbz Val Xan Pro Pro NH 2   
     144. Xeg Val Xan Pro Pro NH 2   
     145. Xca Val Xan Pro Pro NH 2   
     146. Xcb Val Xan Pro Pro NH 2   
     147. Xcc Val Xan Pro Pro NH 2   
     148. Xce Val Xan Pro Pro NH 2   
     149. Xcg Val Xan Pro Pro NH 2   
     150. Xch Val Xan Pro Pro NH 2   
     151. Xci Val Xan Pro Pro NH 2   
     152. Xck Val Xan Pro Pro NH 2   
     153. Xcl Val Xan Pro Pro NH 2   
     154. Xcm Val Xan Pro Pro NH 2   
     155. Xcn Val Xan Pro Pro NH 2   
     156. Xhn Val Xan Pro Pro NH 2   
     157. Xho Val Xan Pro Pro NH 2   
     158. Xhp Val Xan Pro Pro NH 2   
     159. Xhq Val Xan Pro Pro NH 2   
     160. Xaa Val Xan Pro Pro Val Xei 
     161. Xaa Val Xan Pro Pro Val Xem 
     162. Xaa Val Xan Pro Pro Val Xeo 
     153. Xaa Val Xan Pro Pro Val Xep 
     164. Xaa Val Xan Pro Pro Val Xeq 
     165. Xaa Val Xan Pro Pro Val Xex 
     166. Xaa Val Xan Pro Pro Val Xey 
     167. Xaa Val Xan Pro Pro Val Xfb 
     168. Xaa Val Xan Pro Pro Val Xfe 
     169. Xaa Val Xan Pro Pro Val Xfh 
     170. Xaa Val Xan Pro Pro Val Xfu 
     171. Xaa Val Xan Pro Pro Val Xfv 
     172. Xaa Val Xan Pro Pro Val Xft 
     173. Xaa Val Xan Pro Pro Val Xfw 
     174. Xaa Val Xan Pro Pro Val Xfx 
     175. Xaa Val Xan Pro Pro Val Xga 
     176. Xaa Val Xan Pro Pro Val Xgd 
     177. Xaa Val Xan Pro Pro Val Xgg 
     178. Xaa Val Xan Pro Pro Val Xgh 
     179. Xaa Val Xan Pro Pro Val Xgl 
     180. Xaa Val Xan Pro Pro Val Xgl 
     181. Xaa Val Xan Pro Pro Val Xgs 
     182. Xaa Val Xan Pro Pro Val Xgv 
     183. Xaa Val Xan Pro Pro Val Xhe 
     184. Xaa Val Xan Pro Pro Val Xgy 
     185. Xaa Val Xan Pro Pro Val Xhd 
     186. Xaa Val Xan Pro Pro Val Xhb 
     187. Xaa Val Xan Pro Pro Val Xhc 
     188. Xaa Val Xan Pro Pro Val Xhl 
     189. Xaa Val Xan Pro Pro Xeh 
     190. Xaa Val Xan Pro Pro Xen 
     191. Xaa Val Xan Pro Pro Xeo 
     192. Xaa Val Xan Pro Pro Xep 
     193. Xaa Val Xan Pro Pro Xeq 
     194. Xaa Val Xan Pro Pro Xer 
     195. Xaa Val Xan Pro Pro Xet 
     196. Xaa Val Xan Pro Pro Xeu 
     197. Xaa Val Xan Pro Pro Xes 
     198. Xaa Val Xan Pro Pro Xew 
     199. Xaa Val Xan Pro Pro Xez 
     200. Xaa Val Xan Pro Pro Xfc 
     201. Xaa Val Xan Pro Pro Xff 
     202. Xaa Val Xan Pro Pro Xfl 
     203. Xaa Val Xan Pro Pro Xfs 
     204. Xaa Val Xan Pro Pro Xfz 
     205. Xaa Val Xan Pro Pro Xgc 
     206. Xaa Val Xan Pro Pro Xgf 
     207. Xaa Val Xan Pro Pro Xgm 
     208. Xaa Val Xan Pro Pro Xgr 
     209. Xaa Val Xan Pro Pro Xgu 
     210. Xaa Val Xan Pro Pro Xgs 
     211. Xaa Val Xan Pro Pro Xgx 
     212. Xaa Val Xan Pro Pro Xha 
     213. Xaa Val Xan Pro Pro Xhk 
     214. Xaa Val Xan Pro Xek 
     215. Xaa Val Xan Pro Xen 
     216. Xaa Val Xan Pro Xer 
     217. Xaa Val Xan Pro Xep 
     218. Xaa Val Xan Pro Xeq 
     219. Xaa Val Xan Pro Xer 
     220. Xaa Val Xan Pro Xet 
     221. Xaa Val Xan Pro Xeu 
     222. Xaa Val Xan Pro Xes 
     223. Xaa Val Xan Pro Xfa 
     224. Xaa Val Xan Pro Xfd 
     225. Xaa Val Xan Pro Xfg 
     225. Xaa Val Xan Pro Xfl 
     227. Xaa Val Xan Pro Xfk 
     228. Xaa Val Xan Pro Xfm 
     229. Xaa Val Xan Pro Xfn 
     230. Xaa Val Xan Pro Xfo 
     231. Xaa Val Xan Pro Xfp 
     232. Xaa Val Xan Pro Xfq 
     233. Xaa Val Xan Pro Xfr 
     234. Xaa Val Xan Pro Xfy 
     235. Xaa Val Xan Pro Xgb 
     236. Xaa Val Xan Pro Xge 
     237. Xaa Val Xan Pro Xgk 
     238. Xaa Val Xan Pro Xgn 
     239. Xaa Val Xan Pro Xhi 
     240. Xaa Val Xan Pro Xgo 
     241. Xaa Val Xan Pro Xgp 
     242. Xaa Val Xan Pro Xgq 
     243. Xaa Val Xan Pro Xgt 
     244. Xaa Val Xan Pro Xgw 
     245. Xaa Val Xan Pro Xgz 
     246. Xaa Val Xan Pro Xhm 
     247. Xaa Xco Pro Pro Val Phe NH 2   
     248. Xaa Xcp Pro Pro Val Phe NH 2   
     249. Xaa Xcq Pro Pro Val Phe NH 2   
     250. Xaa Xcr Pro Pro Val Phe NH 2   
     251. Xaa Xcs Pro Pro Val Phe NH 2   
     252. Xaa Xct Pro Pro Val Phe NH 2   
     253. Xaa Xcu Pro Pro Val Phe NH 2   
     254. Xaa Xcw Pro Pro Val Phe NH 2   
     255. Xaa Xcv Pro Pro Val Phe NH 2   
     256. Xaa Xcx Pro Pro Val Phe NH 2   
     257. Xaa Xcy Pro Pro Val Phe NH 2   
     258. Xaa Xda Pro Pro Val Phe NH 2   
     259. Xaa Xdb Pro Pro Val Phe NH 2   
     260. Xaa Xdc Pro Pro Val Phe NH 2   
     261. Xaa Xdd Pro Pro Val Phe NH 2   
     262. Xaa Xdf Pro Pro Val Phe NH 2   
     263. Xaa Xdg Pro Pro Val Phe NH 2   
     264. Xaa Xdh Pro Pro Val Phe NH 2   
     265. Xaa Xco Pro Pro Val NH 2   
     266. Xaa Xcp Pro Pro Val NH 2   
     267. Xaa Xcq Pro Pro Val NH 2   
     268. Xaa Xcr Pro Pro Val NH 2   
     269. Xaa Xcs Pro Pro Val NH 2   
     270. Xaa Xct Pro Pro Val NH 2   
     271. Xaa Xcu Pro Pro Val NH 2   
     272. Xaa Xcw Pro Pro Val NH 2   
     273. Xaa Xcv Pro Pro Val NH 2   
     274. Xaa Xcx Pro Pro Val NH 2   
     275. Xaa Xcy Pro Pro Val NH 2   
     276. Xaa Xcz Pro Pro Val NH 2   
     277. Xaa Xda Pro Pro Val NH 2   
     278. Xaa Xdb Pro Pro Val NH 2   
     279. Xaa Xdc Pro Pro Val NH 2   
     280. Xaa Xde Pro Pro Val NH 2   
     281. Xaa Xdf Pro Pro Val NH 2   
     282. Xaa Xdg Pro Pro Val NH 2   
     283. Xaa Xdh Pro Pro Val NH 2   
     284. Xaa Xco Pro Pro NH 2   
     285. Xaa Xcp Pro Pro NH 2   
     286. Xaa Xcq Pro Pro NH 2   
     287. Xaa Xcr Pro Pro NH 2   
     288. Xaa Xcs Pro Pro NH 2   
     289. Xaa Xct Pro Pro NH 2   
     290. Xaa Xcu Pro Pro NH 2   
     291. Xaa Xcw Pro Pro NH 2   
     292. Xaa Xcv Pro Pro NH 2   
     293. Xaa Xcx Pro Pro NH 2   
     294. Xaa Xcy Pro Pro NH 2   
     295. Xaa Xcz Pro Pro NH 2   
     296. Xaa Xda Pro Pro NH 2   
     297. Xaa Xdb Pro Pro NH 2   
     298. Xaa Xdc Pro Pro NH 2   
     299. Xaa Xdd Pro Pro NH 2   
     300. Xaa Xdf Pro Pro NH 2   
     301. Xaa Xdg Pro Pro NH 2   
     302. Xaa Xdh Pro Pro NH 2   
     303. Xds Xan Pro Pro Val Phe NH 2   
     304. Xdt Xan Pro Pro Val Phe NH 2   
     305. Xdu Xan Pro Pro Val Phe NH 2   
     306. Xdv Xan Pro Pro Val Phe NH 2   
     307. Xdw Xan Pro Pro Val Phe NH 2   
     308. Xdx Xan Pro Pro Val Phe NH 2   
     309. Xdy Xan Pro Pro Val Phe NH 2   
     310. Xdz Xan Pro Pro Val Phe NH 2   
     311. Xea Xan Pro Pro Val Phe NH 2   
     312. Xeb Xan Pro Pro Val Phe NH 2   
     313. Xec Xan Pro Pro Val Phe NH 2   
     314. Xds Xan Pro Pro Val NH 2   
     315. Xdt xan Pro Pro Val NH 2   
     316. Xdu Xan Pro Pro Val NH 2   
     317. Xdv Xan Pro Pro Val NH 2   
     318. Xdw Xan Pro Pro Val NH 2   
     319. Xdx Xan Pro Pro Val NH 2   
     320. Xdy Xan Pro Pro Val NH 2   
     321. Xdz Xan Pro Pro Val NH 2   
     322. Xea Xan Pro Pro Val NH 2   
     323. Xeb Xan Pro Pro Val NH 2   
     324. Xed Xan Pro Pro Val NH 2   
     325. Xds Xan Pro Pro NH 2   
     326. Xdt Xan Pro Pro NH 2   
     327. Xdu Xan Pro Pro NH 2   
     328. Xdv Xan Pro Pro NH 2   
     329. Xdw Xan Pro Pro NH 2   
     330. Xdx Xan Pro Pro NH 2   
     331. Xdy Xan Pro Pro NH 2   
     332. Xdz Xan Pro Pro NH 2   
     333. Xea Xan Pro Pro NH 2   
     334. Xeb Xan Pro Pro NH 2   
     335. Xec Xan Pro Pro NH 2   
     336. Xds Val Pro Pro Val Phe NH 2   
     337. Xds Val Pro Pro NH 2   
     338. Xdv Val Pro Pro NH 2   
     339. Xds Xan Pro Xfy 
     340. Xdv Xan Pro Xfy 
     341. Xaa Val Xhf Pro Pro Val Phe NH 2   
     342. Xaa Val Xhg Pro Pro Val Phe NH 2   
     343. Xaa Val Xhh Pro Pro Val Phe NH 2   
     344. Xaa Val Xhf Pro Pro Val NH 2   
     345. Xaa Val Xhg Pro Pro Val NH 2   
     346. Xaa Val Xhh Pro Pro Val NH 2   
     347. Xaa Val Xhf Pro Pro NH 2   
     348. Xaa Val Xhg Pro Pro NH 2   
     349. Xaa Val Xhh Pro Pro NH 2   
     350. Xaa Val Xhf Pro Xfy 
     351. Xaa Val Xhg Pro Xfy 
     352. Xaa Val Xhh Pro Xfy 
     353. Xaa Val Xhf Pro Xgb 
     354. Xaa Val Xhg Pro Xgb 
     355. Xaa Val Xhh Pro Xgb 
     356. Xed Val Xan Pro Xfy 
     357. Xby Val Xan Pro Xfy 
     358. Xby Val Xan Pro Xhi 
     359. Xef Val Xan Pro Xfy 
     360. Xef Val Xan Pro Xhi 
     361. Xca Val Xan Pro Xfy 
     362. Xca Val Xan Pro Xhi 
     363. Xaa Val Xan Pro Xdp Phe NH 2   
     364. Xaa Val Xan Pro Xdq Phe NH 2   
     365. Xaa Val Xan Pro Xdr Phe NH 2   
     366. Xaa Val Xan Pro Xdp NH 2   
     367. Xaa val Xan Pro Xdq NH 2   
     368. Xaa Val Xan Pro Xdr NH 2   
     369. Xaa Val Xan Pro Pro Xdi NH 2   
     370. Xaa Val Xan Pro Pro Xcs NH 2   
     371. Xaa Val Xan Pro Pro Xct NH 2   
     372. Xaa Val Xan Pro Pro Xcu NH 2   
     373. Xaa Xcs Pro Pro Xdi NH 2   
     374. Xaa Xct Pro Pro Xdi NH 2   
     375. Xaa Xcs Pro Xdp Phe NH 2   
     376. Xaa Xct Pro Xdp Phe NH 2   
     377. Xaa Xcs Pro Xdp NH 2   
     378. Xaa Xct Pro Xdp NH 2   
     379. Xaa Xcs Pro Xdq NH 2   
     380. Xaa Xct Pro Xdq NH 2   
     381. Xaa Xcs Pro Xdr NH 2   
     382. Xaa Xct Pro Xdr NH 2   
     383. Xaa Val Xan Pro Pro Xdi NH 2   
     384. Xaa Val Xan Pro Pro Xdk NH 2   
     385. Xaa Val Xan Pro Pro Xdl NH 2   
     386. Xaa Val Xan Pro Pro Xdm NH 2   
     387. Xaa Val Xan Pro Pro Xdn NH 2   
     388. Xaa Val Xan Pro Pro Xdo NH 2   
     389. Xca Val Xan Pro Pro Phe Phe NH 2   
     390. Xby Val Xan Pro Pro Phe Phe NH 2   
     391. Xca Val Xan Pro Pro Phe Phe NH 2   
     392. Xef Val Xhf Pro Pro Xai Phe NH 2   
     393. Xef Val Xhf Pro Pro Xai Xah NH 2   
     394. Xef Val Xhf Pro Pro Xai Xag NH 2   
     395. Xef Val Xan Pro Xfy 
     396. Xef Val Xan Pro Xbg 
     397. Xef Val Xan Pro Xbh 
     398. Xef Val Xan Pro Xgn 
     399. Xca Xct Pro Xfy 
     400. Xaa Xai Xan Pro Pro Val Phe NH 2   
     401. Xaa Leu Xan Pro Pro Val Phe NH 2   
     402. Xaa Ile Xan Pro Pro Val Phe NH 2   
     403. Xaa Val Xan Pro Pro Xai Phe NH 2   
     404. Xaa Val Xan Pro Pro Leu Phe NH 2   
     405. Xaa Val Xan Pro Pro Ile Phe NH 2   
     406. Xaa Val Xan Pro Pro Val Dab NH 2   
     407. Xaa Val Xan Pro Pro Val Ala NH 2   
     408. Xaa Dab Xan Pro Pro Val Phe NH 2   
     409. Xaa Xab Xan Pro Pro Val NH 2   
     410. Xaa Dab Xan Pro Pro NH 2   
     411. Xht Val Xan Pro Pro Val Phe NH 2   
     412. Xhu Val Xan Pro Pro Val Phe NH 2   
     413. Xht Val Xan Pro Pro Val NH 2   
     413. (a). Xhu Val Xan Pro Pro Val NH 2   
     414. Xht Val Xan Pro Pro NH 2   
     415. Xhu Val Xan Pro Pro NH 2   
     416. Xaa Val Xhy Pro Pro Val Phe NH 2   
     417. Xaa Val Xhz Pro Pro Val Phe NH 2   
     418. Xaa Val Xhy Pro Pro Val NH 2   
     419. Xaa Val Xhz Pro Pro Val NH 2   
     420. Xaa Val Xhy Pro Pro NH 2   
     421. Xaa Leu Xhz Pro Pro NH 2   
     422. Xaa Val Xhy Xfy 
     423. Xaa Val Xhz Xfy 
     424. Xhv Val Xan Pro Pro Val Phe NH 2   
     425. Xhw Val Xan Pro Pro Val Phe NH 2   
     426. Xhx Val Xan Pro Pro Val Phe NH 2   
     427. Xhv Val Xan Pro Pro Val NH 2   
     428. Xhw Val Xan Pro Pro Val NH 2   
     429. Xhx Val Xan Pro Pro Val NH 2   
     430. Xhv Val Xan Pro Pro NH 2   
     431. Xhw Val Xan Pro Pro NH 2   
     432. Xhx Val Xan Pro Pro NH 2   
     433. Xaa Val Xan Pro Xia 
     434. Xaa Val Xan Pro Xib 
     435. Xaa Val Xan Pro Xic 
     436. Xaa Val Xan Pro Xid 
     437. Xaa Val Xan Pro Xie 
     438. Xby Val Xan Pro Xia 
     439. Xby Val Xan Pro Xib 
     440. Xby Val Xan Pro Xic 
     441. Xby Val Xan Pro Xid 
     442. Xby Val Xan Pro Xie 
     443. Xca Val Xan Pro Xia 
     444. Xca Val Xan Pro Xib 
     445. Xca Val Xan Pro Xic 
     446. Xca Val Xan Pro Xid 
     447. Xca Val Xan Pro Xie 
     448. Xed Val Xan Pro Xia 
     449. Xed Val Xan Pro Xib 
     450. Xed Val Xan Pro Xic 
     451. Xed Val Xan Pro Xld 
     452. Xed Val Xan Pro Xie 
     453. Xby Leu Xan Pro Xia 
     454. Xby Leu Xan Pro Xib 
     455. Xby Ile Xan Pro Xic 
     455. Xby Ile Xan Pro Xid 
     457. Xby Leu Xan Pro Xie 
     458. Xca Leu Xan Pro Xia 
     459. Xca Val Xao Pro Xib 
     460. Xca Val Xao Pro Xic 
     461. Xat Val Xhf Pro Xak Leu Phe NH 2   
     462. Xat Val Xhf Pro Xhr Leu Phe NH 2   
     463. Xed Val Xhf Pro Xak Leu Phe NH 2   
     464. Xed Val Xhf Pro Xhr Leu Phe NH 2   
     465. Xat Val Xhf Pro Xak Val NH 2   
     466. xat Val Xhf Pro Xhr Val NH 2   
     467. Xed Val Xhf Pro Xak Val NH 2   
     468. Xed Val Xhf Pro Xhr Val NH 2   
     469. Xat Val Xhf Pro Xak NH 2   
     470. Xat Val Xhf Pro Xhr NH 2   
     471. Xed Val Xhf Pro Xak NH 2   
     472. Xat Val Xhf Pro Xia 
     473. Xat Val Xhf Pro Xib 
     474. Xed Val Xhf Pro Xic 
     475. Xed Val Xhf Pro Xid 
     476. Xat Val Xhf Pro Xie 
     477. Xat Val Xhf Pro Xhs NH 2   
     478. Xed Val Xhf Pro Xhs NH 2   
     479. Xat Val Xhf Pro Xak Xfz 
     480. Xat Val Xhf Pro Xhr Xfz 
     481. Xed Val Xhf Pro Xak Xfz 
     482. Xed Val Xhf Pro Xhr Xfz 
     483. Xat Val Xhf Pro Xak Xbw 
     484. Xat Val Xhf Pro Xhr Xbw 
     485. Xed Val Xhf Pro Xak Xbw 
     486. Xed Val Xhf Pro Xhr Xbw 
     487. Xat Val Xhf Pro Xak Xer 
     488. Xat Val Xhf Pro Xhr Xer 
     489. Xed Val Xhf Pro Xak Xer 
     490. Xed Val Xhf Pro Xhr Xer 
     491. Xat Val Xhf Pro Xak Xgi 
     492. Xat Val Xhf Pro Xhr Xgi 
     493. Xed Val Xhf Pro Xak Xgi 
     494. Xed Val Xhf Pro Xhr Xgi 
     495. Xat Val Xhf Pro Xak Xif 
     496. Xat Val Xhf Pro Xhr Xif 
     497. Xed Val Xhf Pro Xak Xif 
     498. Xed Val Xhf Pro Xhr Xif 
     499. Xat Val Xhf Pro Xak Xig 
     500. Xat Val Xhf Pro Xhr Xig 
     501. Xed Val Xhf Pro Xak Xig 
     502. Xed Val Xhf Pro Xhr Xig 
     503. Xaa Val Xan Pro Pro Xlf 
     504. Xaa Val Xan Pro Xig 
     505. Xca Val Xan Pro Pro Xif 
     506. Xca Val Xan Pro Xlg 
     507. Xby Val Xan Pro Pro Xif 
     508. Xby Val Xan Pro Xig 
     509. Xed Val Xan Pro Pro Xif 
     510. Xed Val Xan Pro Xig 
     511. Xaa Leu Xan Pro Pro Xif 
     512. Xaa Leu Xan Pro Xig 
     513. Xca Leu Xan Pro Pro Xif 
     514. Xca Leu Xan Pro Xig 
     515. Xby Leu Xan Pro Pro Xif 
     516. Xby Leu Xan Pro Xig 
     517. Xed Leu Xan Pro Pro Xif 
     518. Xed Leu Xan Pro Xig 
     519. Xaa Lys Xan Pro Pro Val Phe NH 2   
     520. Xaa Lys Xan Pro Pro Val NH 2   
     521. Xaa Lys Xan Pro Pro NH 2   
     522. Xaa Lys Xan Pro Xfy 
     523. Xaa Xih Xan Pro Pro Val NH 2   
     524. Xaa Xih Xan Pro Pro NH 2   
     525. Xaa Xih Xan Pro Pro Val Phe NH 2   
     525. Xaa Val Xii Pro Pro Val Phe NH 2   
     527. Xaa Val Xii Pro Pro Val NH 2   
     528. Xaa Val Xii Pro Pro NH 2   
     529. Xaa Val Xan Pro Pro Val Lys NH 2   
     530. Xaa Val Xan Pro Xik 
     531. Xaa Val Xan Pro Pro Xil NH 2   
     532. Xaa Val Xbu 
     533. Xby Val Xbu 
     534. Xca Val Xbu 
     535. Xaa Val Xbv 
     536. Xby Val Xbv 
     537. Xca Val Xbv 
     538. Xaa Val Xan Pro Pro Xab 
     539. Xaa Val Xan Xab 
     540. Xim Val Xan Pro Pro Val Phe NH 2   
     541. Xin Val Xan Pro Pro Val Phe NH 2   
     542. Xio Val Xan Pro Pro Val Phe NH 2   
     543. Xip Val Xan Pro Pro Val Phe NH 2   
     544. Xiq Val Xan Pro Pro Val Phe NH 2   
     545. Xkd Val Xan Pro Pro Val Phe NH 2   
     546. Xim Val Xan Pro Pro Val NH 2   
     547. Xin Val Xan Pro Pro Val NH 2   
     548. Xio Val Xan Pro Pro Val NH 2   
     549. Xip Val Xan Pro Pro Val NH 2   
     550. Xiq Val Xan Pro Pro Val NH 2   
     551. Xkd Val Xan Pro Pro Val NH 2   
     552. Xim Val Xan Pro Pro NH 2   
     553. Xin Val Xan Pro Pro NH 2   
     554. Xio Val Xan Pro Pro NH 2   
     555. Xip Val Xan Pro Pro NH 2   
     556. Xiq Val Xan Pro Pro NH 2   
     557. Xkd Val Xan Pro Pro NH 2   
     558. Xaa Val Xan Pro Pro Val Xir 
     559. Xaa Val Xan Pro Pro Val Xis 
     560. Xaa Val Xan Pro Pro Val Xit 
     561. Xaa Val Xan Pro Pro Val Xiu 
     562. Xaa Val Xan Pro Pro Xiv 
     563. Xaa Val Xan Pro Pro Xiw 
     564. Xaa Val Xan Pro Pro Xiy 
     565. Xaa Val Xan Pro Pro Xix 
     566. Xaa Val Xan Pro Xiz 
     567. Xaa Val Xan Pro Xka 
     568. Xaa Val Xan Pro Xkb 
     569. Xaa Val Xan Pro Xkc 
     570. Xke Val Xan Pro Pro Val Phe NH 2   
     571. Xkf Val Xan Pro Pro Val Phe NH 2   
     572. Xkg Val Xan Pro Pro Val Phe NH 2   
     573. Xkh Val Xan Pro Pro Val Phe NH 2   
     574. Xke Val Xan Pro Pro Val NH 2   
     575. Xkf Val Xan Pro Pro Val NH 2   
     576. Xkg Val Xan Pro Pro Val NH 2   
     577. Xkh Val Xan Pro Pro Val NH 2   
     578. Xke Val Xan Pro Pro NH 2   
     579. Xkf Val Xan Pro Pro NH 2   
     580. Xkg Val Xan Pro Pro NH 2   
     581. Xkh Val Xan Pro Pro NH 2   
     582. Xaa Xcz Pro Pro Val Phe NH 2   
     583. Xed Val Xhf Pro Xhr NH 2   
     584. Val Val Xan Pro Pro Val Phe 
     585. Xaa Val Xan Pro Pro Val 
     586. Xaa Val Xki Pro Pro Val Phe NH 2   
     587. Xaa Val Xan Pro Pro Val Xhz NH 2   
     588. Xaa Val Xan Pro Pro Val Xah NH 2   
     589. Xaa Val Xan Pro Pro Val Tyr NH 2   
     590. Xaa Val Xan Pro Pro Phe Phe NH 2   
     591. Xaa Val Xan Pro Pro Val Xkj NH 2   
     592. Xaa Val Xan Xbb 
     593. Xaa Val Xan Pro Pro Xab 
     594. Xaa Val Xan Xfp 
     595. Xaa Val Xan Xbg 
     596. Xaa Val Xan Xbx 
     597. Xaa Val Xan Pro Xbg 
     598. Xaa Val Xan Pro Pro Ile NH 2   
     599. Xaa Val Xan Pro Pro Leu NH 2   
     600. Xaa Val Xan Pro Pro Xlv NH 2   
     601. Xaa Val Xan Xfo 
     602. Xaa Val Xan Pro Pro Xlw Phe NH 2   
     603. Xaa Val Xan Pro Pro Xlx Phe NH 2   
     604. Xaa Val Xan Pro Pro Val Xlw NH 2   
     605. Xaa Val Xan Pro Xkr 
     606. Xar Val Xan Pro Xfy 
     607. Xat Xai Xan Pro Xfy 
     608. Xaa Val Xan Pro Pro Val Xlv NH 2   
     609. Xaa Val Xan Pro Xkc 
     610. Xaa Val Xan Pro Xbm 
     611. Xaa Val Xan Pro Xka 
     612. Xaa Val Xan Pro Xks 
     613. Xaa Val Xan Pro Xiz 
     614. Xaa Val Xan Pro Xbk 
     615. Xaa Val Xan Pro Xen 
     616. Xaa Val Xan Pro Xhi 
     617. Xaa Val Xan Pro Xbh 
     618. Xaa Val Xan Pro Xfd 
     619. Xaa Val Xan Pro Xgn 
     620. Xbo Val Xan Pro Xfy 
     621. Xat Val Xan Pro Xfy 
     622. Xas Val Xan Pro Xfy 
     623. Xaa Val Xam Pro Xfy 
     624. Xcl Val Xan Pro Xfy 
     625. Xci Val Xan Pro Xfy 
     626. Xaa Val Xhz Pro Xfy 
     627. Xaa Val Xan Pro Xkt 
     628. Xaa Val Xan Pro Xku 
     629. Xaa Val Xan Pro Xkv 
     630. Xaa Val Xan Pro Xkw 
     631. Xaa Val Xhh Pro Xfy 
     632. Xaa Ile Xan Pro Xfy 
     633. Xaa Val Xan Xak Xfy 
     634. Xaa Val Xan Pro Xkb 
     635. Xat Val Xan Pro Xbg 
     636. Xar Val Xan Pro Xbg 
     637. Xar Val Xam Pro Xfy 
     638. Xaa Val Xan Pro Pro Xga 
     639. Xaa Val Xan Pro Xkx 
     640. Xaa Val Xan Pro Pro Leu Phe NH 2   
     641. Xaa Val Xan Pro Pro Ile Phe NH 2   
     642. Xaa Val Xan Pro Xky 
     643. Xaa Val Xan Pro Xkz 
     644. Xaa Val Xan Pro Xfr 
     645. Xaa Val Xam Pro Pro NH 2   
     646. Xaa Val Xan Pro Xla 
     647. Xaa Val Xan Pro Xlb 
     648. Xaa Val Xan Pro Xlc 
     649. Xaa Val Xan Pro Xld 
     650. Xaa Val Xan Pro Xkk 
     651. Xaa Val Xan Pro Xek 
     652. Xaa Val Xan Pro Xle 
     653. Xaa Val Xan Pro Xlf 
     654. Xaa Val Xan Pro Xlg 
     655. Xaa Val Xan Pro Xkl 
     656. Xaa Val Xan Pro Xlh 
     657. Xkm Val Xan Pro Xfy 
     658. Xaa Val Xan Pro Xli 
     659. Xaa Val Xan Pro Xlk 
     660. Xkn Val Xan Pro Xfy 
     661. Xaa Val Xan Pro Xll 
     662. Xaa Val Xan Pro Xlm 
     663. Xaa Val Xan Pro Xfk 
     664. Xaa Xma Xan Pro Xfy 
     665. Xaa Val Xhg Pro Xfy 
     666. Xaa Val Xhy Pro Xfy 
     667. Xaa Val Xan Pro Xln 
     668. Xaa Xai Xan Pro Xfy 
     669. Xaa Val Xao Pro Xfy 
     670. Xaa Val Xan Pro Xlo 
     671. Xaa Val Xan Pro Xko 
     672. Xaa Val Xan Pro Xkp 
     673. Xaa Val Xan Pro Xlp 
     674. Xaa Val Xan Pro Xlq 
     675. Xaa Val Xan Pro Pro Xlr 
     676. Xaa Val Xhf Pro Xfy 
     677. Xaa Val Xan Pro Xls 
     678. Xaa Val Xan Pro Xlt 
     679. Xby Val Xan Pro Xfy 
     680. Xkq Val Xan Pro Xfy 
     681. Xaa Val Xan Pro Xlu 
     Examples for the MS-characterization of the synthesized novel compounds are given in the following table. 
     
         ______________________________________                                    
EXAMPLE    Fast atom bombardment MS analysis.                             
 No.!       Mol.-Weight (measured)!                                       
______________________________________                                    
3.         798                                                            
16.        810                                                            
19.        812                                                            
20.        812                                                            
23.        812                                                            
25.        812                                                            
26.        812                                                            
28.        811                                                            
30.        825                                                            
33.        881                                                            
34.        845                                                            
37.        649                                                            
38.        737                                                            
50.        550                                                            
51.        551                                                            
52.        731                                                            
56.        550                                                            
65.        566                                                            
66.        566                                                            
87.        635                                                            
93.        704                                                            
101.       853                                                            
204.       740                                                            
214.       619                                                            
215.       845                                                            
227.       649                                                            
230.       691                                                            
233.       717                                                            
234.       641                                                            
239.       579                                                            
246.       595                                                            
347.       566                                                            
349.       566                                                            
351.       669                                                            
352.       656                                                            
357.       669                                                            
403.       811                                                            
404.       812                                                            
405.       812                                                            
597.       635                                                            
598.       665                                                            
699.       665                                                            
600.       749                                                            
601.       594                                                            
602.       852                                                            
603.       826                                                            
604.       804                                                            
605.       677                                                            
606.       655                                                            
607.       670                                                            
608.       848                                                            
609.       608                                                            
610.       627                                                            
611.       565                                                            
612.       633                                                            
613.       642                                                            
614.       642                                                            
615.       731                                                            
616.       657                                                            
617.       647                                                            
618.       648                                                            
619.       663                                                            
620.       669                                                            
621.       655                                                            
622.       655                                                            
623.       655                                                            
624.       681                                                            
625.       667                                                            
626.       689                                                            
627.       565                                                            
628.       579                                                            
629.       593                                                            
630.       594                                                            
631.       659                                                            
632.       655                                                            
633.       655                                                            
634.       580                                                            
635.       648                                                            
636.       648                                                            
637.       669                                                            
638.       788                                                            
639.       647                                                            
640.       812                                                            
641.       812                                                            
642.       668                                                            
643.       709                                                            
644.       717                                                            
645.       566                                                            
646.       684                                                            
647.       657                                                            
648.       684                                                            
649.       634                                                            
650.       630                                                            
651.       619                                                            
652.       699                                                            
653.       608                                                            
654.       655                                                            
655.       680                                                            
656.       590                                                            
657.       670                                                            
658.       655                                                            
659.       669                                                            
660.       627                                                            
661.       607                                                            
662.       621                                                            
663.       649                                                            
664.       627                                                            
665.       669                                                            
666.       695                                                            
667.       628                                                            
668.       655                                                            
669.       655                                                            
670.       607                                                            
671.       646                                                            
672.       660                                                            
673.       685                                                            
674.       628                                                            
675.       754                                                            
676.       656                                                            
677.       635                                                            
678.       621                                                            
679.       669                                                            
680.       656                                                            
681.       667                                                            
______________________________________                                    
 
    
     
                       TABLE I                                                     
______________________________________                                    
Sequence Identification of Compounds Prepared                             
According to Examples 1 and 2                                             
Compound Number(s)    Sequence ID Number                                  
______________________________________                                    
3, 9, 26-28, 30-33, 35, 36,                                               
                      1                                                   
95-117, 341-343, 416, 417,                                                
424-426, 526, 540-545, 570-573, 586                                       
38, 39, 52, 86-91, 93, 214-246,                                           
                      2                                                   
350-362, 366-368, 395-398,                                                
433-452, 459, 460, 469-478,                                               
504, 506, 508, 510, 530,                                                  
566-569, 583, 597, 606, 607, 609-611,                                     
613-626, 631, 633-637, 644, 650,                                          
651, 654, 655, 657, 660, 663, 665,                                        
666, 669, 671, 672, 676, 679, 680                                         
605, 612, 627, 628-630, 639, 642, 643,                                    
645-649, 652, 653, 656, 658, 659, 661,                                    
662, 667, 670, 673, 674, 677, 678, 681                                    
4-7, 10, 11, 160-188, 406, 558-561, 587,                                  
                      3                                                   
588, 591, 604, 608                                                        
8                     4                                                   
12                    5                                                   
13, 392, 403, 602, 603                                                    
                      6                                                   
14, 641               7                                                   
15, 16, 29            8                                                   
17, 18                9                                                   
19, 20                10                                                  
21, 22, 247-264, 303-313, 582                                             
                      11                                                  
23, 402               12                                                  
24, 400               13                                                  
25, 401               14                                                  
34, 590               15                                                  
37, 118-138, 344-346, 585                                                 
                      16                                                  
40, 45, 189-213, 369-372, 383-388,                                        
                      17                                                  
503, 505, 507, 509, 531, 538, 563-565,                                    
593, 600, 638, 675                                                        
41-43, 48, 49, 527    18                                                  
44                    19                                                  
46, 50, 51, 62-65, 70, 139-159, 347-349                                   
                      20                                                  
414, 415, 420, 421, 430-432, 528,                                         
552-557, 578-581                                                          
47                    21                                                  
53-61, 78, 422, 423, 539, 592, 594-596                                    
                      22                                                  
601                                                                       
66, 67, 94, 410, 524  23                                                  
68, 69, 284-302, 325-335                                                  
                      24                                                  
73, 83-85             25                                                  
92, 664, 668          26                                                  
265-283, 314-324      27                                                  
336                   28                                                  
337, 338              29                                                  
339, 340, 377-382, 399                                                    
                      30                                                  
363-365               31                                                  
373, 374              32                                                  
375, 376              33                                                  
389-391               34                                                  
393, 394              35                                                  
404, 640              36                                                  
405                   37                                                  
407                   38                                                  
408                   39                                                  
409                   40                                                  
411, 412, 418, 419, 427-429,                                              
                      41                                                  
546-551, 574-577                                                          
413, 413(a), 453, 454, 457,                                               
                      42                                                  
458, 512 514, 516, 518                                                    
455, 456, 632         43                                                  
465-468               44                                                  
461-464               45                                                  
479-502               46                                                  
515, 517              47                                                  
513                   48                                                  
519                   49                                                  
520                   50                                                  
521                   51                                                  
522                   52                                                  
523                   53                                                  
525                   54                                                  
529                   55                                                  
584                   56                                                  
589                   57                                                  
598                   58                                                  
599                   59                                                  
______________________________________                                    
 
    
     The symbols Xaa . . . in the summary have the following meanings: ##STR5## 
     The ending --NH 2  has the meaning that the C-terminal amino acid is in its amide form. 
     Compounds of this invention may be assayed for anti-cancer activity by conventional methods, including for example, the methods described below. 
     A. In vitro methodology 
     Cytotoxicity was measured using a standard methodology for adherent cell lines such as the microculture tetrazolium assay (MTT). Details of this assay have been published (Alley, MC et al, Cancer Research 48:589-601, 1988). Exponentially growing cultures of tumor cells such as the HT-29 colon carcinoma or LX-1 lung tumor are used to make microtiter plate cultures. Cells are seeded at 5000-20,000 cells per well in 96-well plates (in 150 μl of media), and grown overnight at 370° C. Test compounds are added, in 10-fold dilutions varying from 10 -4  M to 10 -10  M. Cells are then incubated for 48 hours. To determine the number of viable cells in each well, the MTT dye is added (50 μl of 3 mg/ml solution of 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide in saline). This mixture is incubated at 370° C. for 5 hours, and then 50 μl of 25% SDS, pH2 is added to each well. After an overnight incubation, the absorbance of each well at 550 nm is read using an ELISA reader. The values for the mean ±SD of data from replicated wells are calculated, using the formula % T/C (% viable cells treated/control). ##EQU1## The concentration of test compound which gives a T/C of 50% growth inhibition was designated as the IC 50  value. The following results were obtained: 
     
         ______________________________________                                    
COMPOUND OF EXAMPLE                                                       
                   IC.sub.50  M!                                          
______________________________________                                    
14                 3 × 10.sup.-7                                    
19                 8 × 10.sup.-5                                    
20                 2 × 10.sup.-9                                    
21                 &gt;10.sup.-4                                             
23                 2 × 10.sup.-5                                    
25                 2 × 10.sup.-4                                    
26                 6 × 10.sup.-8                                    
27                 5 × 10.sup.-6                                    
29                 &gt;10.sup.-4                                             
30                 &gt;10.sup.-4                                             
52                 5 × 10.sup.-5                                    
55                 2 × 10.sup.-6                                    
56                 4 × 10.sup.-7                                    
57                 4 × 10.sup.-6                                    
58                   10.sup.-5                                            
62                 3 × 10.sup.-5                                    
65                 4 × 10.sup.-7                                    
66                 2 × 10.sup.-7                                    
68                 6 × 10.sup.-7                                    
73                 2 × 10.sup.-5                                    
86                   10.sup.-7                                            
87                 4 × 10.sup.-8                                    
88                 2 × 10.sup.-9                                    
93                 5 × 10.sup.-9                                    
94                 &gt;10.sup.-4                                             
95                 5 × 10.sup.-7                                    
102                  10.sup.-4                                            
146                2 × 10.sup.-5                                    
157                2 × 10.sup.-4                                    
204                4 × 10.sup.-9                                    
214                  10.sup.-9                                            
215                3 × 10.sup.-9                                    
227                  10.sup.-8                                            
230                  10.sup.-9                                            
233                  10.sup.-9                                            
234                .sup. 3 × 10.sup.-10                             
238                6 × 10.sup.-7                                    
239                6 × 10.sup.-8                                    
241                &gt;10.sup.-6                                             
246                  10.sup.-8                                            
247                &gt;10.sup.-4                                             
284                6 × 10.sup.-7                                    
339                &gt;10.sup.-6                                             
340                &gt;10.sup.-6                                             
347                3 × 10.sup.-7                                    
349                6 × 10.sup.-7                                    
351                7 × 10.sup.-8                                    
352                2 × 10.sup.-8                                    
357                8 × 10.sup.-9                                    
361                &gt;10.sup.-6                                             
400                2 × 10.sup.-4                                    
404                4 × 10.sup.-7                                    
405                3 × 10.sup.-7                                    
411                &gt;10.sup.-5                                             
417                2 × 10.sup.-5                                    
521                &gt;10.sup.-4                                             
______________________________________                                    
 
    
     Further compounds of this invention were assayed for anti-cancer activity by the crystal violet assay for cytotoxicity. 
     This assay was performed according to the method described by Flick H. and Gifford, G. E., J. Immunol. Meth. 68, 167-175 (1984). Proteins of surviving adherent cells are stained after exposure to a cytotoxic drug and quantitated calorimetrically. Test cells (CX-I; colon carcinoma, human) were plated in 96 flat bottom microtiter plates at a density of 2-3×10 3  cells/well and incubated under standard culture conditions (RPMI 1640 with 10% fetal calf serum and 1% non-essential amino acids) at 37° C. and 5% CO 2  for one day. The cells were then exposed to several concentrations of the test compound. Controls were incubated in medium alone. After a further incubation period of 72 h, the culture medium was removed by flicking and 50 μl of a crystal violet staining solution were added to each well. After a staining period of 20 min, the staining solution was removed and the plates were washed vigorously with water until all unbound dye was removed. The remaining insoluble dye crystals were dissolved by adding 100 μl of a solution containing 50% ethanol and 0.1% acetic acid to each well. The absorbance of each well was determined using an ELISA microtiter plate reader at 540 nm (Titertec Multiscan, Flow Lab., Meckenheim). 
     The concentration of test compound which gives a T/C of 50% growth inhibition was designated as the IC 50 . The following results were obtained: 
     
         ______________________________________                                    
COMPOUND OF EXAMPLE                                                       
                   IC.sub.50  M!                                          
______________________________________                                    
1                  9 × 10.sup.-8                                    
2                  4 × 10.sup.-8                                    
3                  6 × 10.sup.-7                                    
8                  5 × 10.sup.-6                                    
9                  4 × 10.sup.-8                                    
10                 6 × 10.sup.-8                                    
13                 2 × 10.sup.-7                                    
16                 9 × 10.sup.-7                                    
28                 3 × 10.sup.-8                                    
31                 10.sup.-5                                              
33                 2 × 10.sup.-5                                    
34                 4 × 10.sup.-8                                    
36                 2 × 10.sup.-5                                    
37                 4 × 10.sup.-7                                    
38                 .sup. 3 × 10.sup.-10                             
48                 4 × 10.sup.-7                                    
50                 2 × 10.sup.-7                                    
51                 5 × 10.sup.-7                                    
59                 8 × 10.sup.-6                                    
101                2 × 10.sup.-4                                    
406                4 × 10.sup.-7                                    
407                9 × 10.sup.-7                                    
408                2 × 10.sup.-6                                    
538                10.sup.-10                                             
______________________________________                                    
 
    
     B. In vivo methodology 
     Compounds of this invention were further tested in pre-clinical assay for in vivo activity which is indicative of clinical utility. Such assays were conducted with nude mice into which tumor tissue, preferably of human origin, had been transplanted (xenografted), as is well known in this field. Test compounds were evaluated for their anti-tumor efficacy following administration to the xenograft-bearing mice. 
     More specifically, human breast tumors (MX-1) which had been grown in athymic nude mice were transplanted into new recipient mice, using tumor fragments which were about 50 mg in size. The day of transplantation was designated as day 0. Six to ten days later, mice were treated with the test compounds given as an intravenous injection, in groups of 5-10 mice at each dose. Compounds were given every other day, for 3 weeks, at doses from 1-100 mg/kg body weight. Tumor diameters and body weights were measured twice weekly. Tumor volumes were calculated using the diameters measured with Vernier calipers, and the formula 
     
         (length×width.sup.2)/2=mm.sup.3 of tumor volume 
    
     Mean tumor volumes are calculated for each treatment group, and T/C values determined for each group relative to the untreated control tumors. 
     In the second example as shown in FIG. 2., mice were treated with compound example #234, at 25 mg/kg 3 times a week for 3 weeks. All tumors in the treated group disappeared, while the control tumors grew so large the mice were sacrificed. No regrowth of the tumor was observed in the treated mice. 
     Representative Compounds Tested in Vivo 
     Additional compounds were also tested in the MX-1 model as described above. Compounds were administered i.v. Compounds which had good activity in the MX-1 model were also tested in additional in vivo models. 
     
         ______________________________________                                    
EXAMPLE      ACTIVITY*   COMMENTS                                         
______________________________________                                    
2            +           tumor growth delay                               
37           ++          regressions,                                     
                         active in other models                           
38           +++         cures, active in other                           
                         models                                           
50           +++         cures, active in other                           
                         models                                           
230          ++          regressions                                      
595          +++         cures, active in other                           
                         models                                           
610          ++          regressions                                      
611          ++          regressions                                      
627          +++         cures, active in other                           
                         models                                           
629          +++         cures, active in other                           
                         models                                           
______________________________________                                    
  *!:                                                                     
 + tumor growth delay                                                     
 ++ regressions                                                           
 +++ cures                                                                
 other models P388 leukemia, OVCAR ovarian carcinoma, LOX human melanoma  
 
    
     These data show that the new compounds possess good tumor inhibiting properties. 
     
         __________________________________________________________________________
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XaaValXaaProProValPhe                                                     
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XaaValXaaProXaa                                                           
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XaaValXaaProProValXaa                                                     
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XaaValXaaProProValHis                                                     
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XaaXaaXaaProProValTrp                                                     
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XaaValXaaProProXaaPhe                                                     
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XaaValXaaProProIlePhe                                                     
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XaaValXaaProXaaValPhe                                                     
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XaaValXaaXaaProValPhe                                                     
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XaaValXaaProProValPhe                                                     
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XaaXaaProProValPhe                                                        
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XaaIleXaaProProValPhe                                                     
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XaaXaaXaaProProValPhe                                                     
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XaaLeuXaaProProValPhe                                                     
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XaaValXaaProProPhePhe                                                     
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XaaValXaaProProVal                                                        
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XaaValXaaProProXaa                                                        
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XaaValXaaProProVal                                                        
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XaaXaaXaaProProVal                                                        
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XaaValXaaXaaProVal                                                        
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XaaValXaaProXaaVal                                                        
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XaaValXaaXaa                                                              
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(A) LENGTH: 5 amino acids                                                 
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XaaXaaXaaProPro                                                           
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(A) LENGTH: 4 amino acids                                                 
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XaaXaaProPro                                                              
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XaaValXaaPro                                                              
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(A) LENGTH: 5 amino acids                                                 
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XaaXaaXaaProXaa                                                           
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XaaXaaProProVal                                                           
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(A) LENGTH: 6 amino acids                                                 
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XaaValProProValPhe                                                        
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XaaValProPro                                                              
1                                                                         
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(A) LENGTH: 4 amino acids                                                 
(B) TYPE: amino acid                                                      
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XaaXaaProXaa                                                              
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(A) LENGTH: 6 amino acids                                                 
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XaaValXaaProXaaPhe                                                        
15                                                                        
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(A) LENGTH: 5 amino acids                                                 
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XaaXaaProProXaa                                                           
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XaaXaaProXaaPhe                                                           
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XaaValXaaProProPhePhe                                                     
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XaaValXaaProProXaaXaa                                                     
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(A) LENGTH: 7 amino acids                                                 
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XaaValXaaProProLeuPhe                                                     
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XaaValXaaProProIlePhe                                                     
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(A) LENGTH: 7 amino acids                                                 
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XaaValXaaProProValAla                                                     
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XaaXaaXaaProProValPhe                                                     
15                                                                        
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XaaXaaXaaProProVal                                                        
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(A) LENGTH: 7 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                                  
XaaValXaaProProValPhe                                                     
15                                                                        
(2) INFORMATION FOR SEQ ID NO:42:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 6 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                                  
XaaValXaaProProVal                                                        
15                                                                        
(2) INFORMATION FOR SEQ ID NO:43:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 5 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                                  
XaaIleXaaProXaa                                                           
15                                                                        
(2) INFORMATION FOR SEQ ID NO:44:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 6 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                                  
XaaValXaaProXaaVal                                                        
15                                                                        
(2) INFORMATION FOR SEQ ID NO:45:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 7 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                                  
XaaValXaaProXaaLeuPhe                                                     
15                                                                        
(2) INFORMATION FOR SEQ ID NO:46:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 6 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                                  
XaaValXaaProXaaXaa                                                        
15                                                                        
(2) INFORMATION FOR SEQ ID NO:47:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 6 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                                  
XaaLeuXaaProProXaa                                                        
15                                                                        
(2) INFORMATION FOR SEQ ID NO:48:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 6 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                                  
XaaLeuXaaProProXaa                                                        
15                                                                        
(2) INFORMATION FOR SEQ ID NO:49:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 7 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                                  
XaaLysXaaProProValPhe                                                     
15                                                                        
(2) INFORMATION FOR SEQ ID NO:50:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 6 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                                  
XaaLysXaaProProVal                                                        
15                                                                        
(2) INFORMATION FOR SEQ ID NO:51:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 5 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                                  
XaaLysXaaProPro                                                           
15                                                                        
(2) INFORMATION FOR SEQ ID NO:52:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 5 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                                  
XaaLysXaaProXaa                                                           
15                                                                        
(2) INFORMATION FOR SEQ ID NO:53:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 6 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                                  
XaaXaaXaaProProVal                                                        
15                                                                        
(2) INFORMATION FOR SEQ ID NO:54:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 7 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                                  
XaaXaaXaaProProValPhe                                                     
15                                                                        
(2) INFORMATION FOR SEQ ID NO:55:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 7 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                                  
XaaValXaaProProValLys                                                     
15                                                                        
(2) INFORMATION FOR SEQ ID NO:56:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 7 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                                  
XaaValXaaProProValPhe                                                     
15                                                                        
(2) INFORMATION FOR SEQ ID NO:57:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 7 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                                  
XaaValXaaProProValTyr                                                     
15                                                                        
(2) INFORMATION FOR SEQ ID NO:58:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 6 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                                  
XaaValXaaProProIle                                                        
15                                                                        
(2) INFORMATION FOR SEQ ID NO:59:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 6 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) STRANDEDNESS:                                                         
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:                                  
XaaValXaaProProLeu                                                        
15                                                                        
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