Compounds and methods for modulating cell adhesion

Abstract

Cyclic peptides comprising a cadherin cell adhesion recognition sequence HAV, and compositions comprising such cyclic peptides, are provided. Methods for using such peptides for modulating cadherin-mediated cell adhesion in a variety of contexts are also provided.

1 . A cyclic peptide having the formula:  
       
         
           
           
               
               
           
         
         wherein X 1 , and X 2  are optional, and if present, are independently selected from the group consisting of amino acid residues and combinations thereof in which the residues are linked by peptide bonds, and wherein X 1  and X 2  independently range in size from 0 to 10 residues, such that the sum of residues contained within X 1  and X 2  ranges from 1 to 12; wherein Y 1  and Y 2  are independently selected from the group consisting of amino acid residues and wherein a covalent bond is formed between residues Y 1  and Y 2 ; and wherein Z 1  and Z 2  are optional, and if present, are independently selected from the group consisting of amino acid residues and combinations thereof in which the residues are linked by peptide bonds.  
       
     
     
         2 . A cyclic peptide according to  claim 1 , the peptide has an N-terminal acetyl, formyl or mesyl group.  
     
     
         3 . A cyclic peptide according to  claim 1 , wherein X and Y are each independently selected from the group consisting of cysteine, penicillamine, β,β-tetramethylene cysteine, β,β-pentamethylene cysteine, β-mercaptopropionic acid, β,β-pentamethylene-β-mercaptopropionic acid, 2-mercaptobenzene, 2-mercaptoaniline and 2-mercaptoproline.  
     
     
         4 . A cyclic peptide according to  claim 1 , wherein X and Y are cysteine residues.  
     
     
         5 . A cyclic peptide according to  claim 1 , wherein the cyclic peptide comprises a sequence selected from the group consisting of: N—Ac- CHAVC -NH 2  (SEQ ID NO:10), N—Ac- CHAVC -Y—NH 2  (SEQ ID NO:84), N—N—Ac- CHAVDC -NH 2  (SEQ ID NO:20), N—Ac- CHAVDIC -NH 2  (SEQ ID NO:50), N—Ac- CHAVDINC -NH 2  (SEQ ID NO:51), N—Ac- CHAVDINGC -NH 2  (SEQ ID NO:76), N—Ac- CAHAVC -NH 2  (SEQ ID NO:22), N—Ac- CAHAVDC -NH 2  (SEQ ID NO:26), N—Ac- CAHAVDIC -NH 2  (SEQ ID NO:24), N—Ac- CRAHAVDC -NH 2  (SEQ ID NO:28), N—Ac- CLRAHAVC -NH 2  (SEQ ID NO:30), N—Ac- CLRAHAVDC -NH 2  (SEQ ID NO:32), N—Ac- CSHAVC -NH 2  (SEQ ID NO:36), N—Ac- CFSHAVC -NH 2  (SEQ ID NO:85), N—Ac- CLFSHAVC -NH 2  (SEQ ID NO: — 86), N—Ac- CHAVSC -NH 2  (SEQ ID NO:38), N—Ac- CSHAVSC -NH 2  (SEQ ID NO:40), N—Ac- CSHAVSSC -NH 2  (SEQ ID NO:42), N—Ac- CHAVSSC -NH 2  (SEQ ID NO:44), N—Ac- KHAVD -NH 2  (SEQ ID NO:12), N—Ac- DHAVK -NH 2  (SEQ ID NO:14), N—Ac- KHAVE -NH 2  (SEQ ID NO:16), N—Ac- AHAVDI -NH 2  (SEQ ID NO:34), N—Ac- SHAVDSS -NH 2  (SEQ ID NO:77), N—Ac- KSHAVSSD -NH 2  (SEQ ID NO:48), N—Ac- CHAVC -S—NH 2  (SEQ ID NO:87), N—Ac—S- CHAVC -NH 2  (SEQ ID NO:88), N—Ac- CHAVC -SS—NH 2  (SEQ ID NO:89), N—Ac—S- CHAVC -S—NH 2  (SEQ ID NO:90), N—Ac- CHAVC -T-NH 2  (SEQ ID NO:91), N—Ac- CHAVC -E-NH 2  (SEQ ID NO:92), N—Ac- CHAVC -D-NH 2  (SEQ ID NO:93), N—Ac- CHAVYC -NH 2  (SEQ ID NO:94), CH 3 —SO 2 -HN- CHAVC -Y—NH 2  (SEQ ID NO:95), CH 3 —SO 2 —HN- CHAVC -NH 2  (SEQ ID NO:96), HC(O)—NH- CHAVC -NH 2  (SEQ ID NO:96), N—Ac- CHAVPen -NH 2  (SEQ ID NO:97), N—Ac- PenHAVC -NH 2  (SEQ ID NO:98) and N—Ac- CHAVPC -NH 2 . (SEQ ID NO:99).  
     
     
         6 . A cyclic peptide according to  claim 5 , wherein the cyclic peptide has an N-terminal acetyl group or CH 3 —SO 2 — group, and a C-terminal amide group.  
     
     
         7 . A cyclic peptide comprising a dimer or multimer of the sequence His-Ala-Val.  
     
     
         8 . A cell adhesion modulating agent comprising a cyclic peptide according to any one of claims  1 - 7 .  
     
     
         9 - 33 . (canceled)  
     
     
         34 . A method for modulating vascular smooth muscle cell migration, comprising contacting a vascular smooth muscle cell with a cell adhesion modulating agent according to  claim 8 , and thereby modulating vascular smooth muscle cell migration.  
     
     
         35 . A method for modulating vascular smooth muscle cell apoptosis, comprising contacting a vascular smooth muscle cell with a cell adhesion modulating agent according to  claim 8 , and thereby modulating vascular smooth muscle cell apoptosis.  
     
     
         36 . A method for preventing the formation or advance of restenosis, comprising contacting a cadherin expressing cell with a cell adhesion modulating agent according to  claim 8 , and thereby preventing the formation or advance of restenosis.  
     
     
         37 . A method for maintaining vessel luminal area following vascular trauma, comprising contacting a cadherin expressing cell with a cell adhesion modulating agent according to  claim 8 , and thereby maintaining vessel luminal area following vascular trauma.  
     
     
         38 . A method for treating a traumatized vessel, comprising contacting a cadherin expressing cell with a cell adhesion modulating agent according to  claim 8 , and thereby treating a traumatized vessel.  
     
     
         39 - 51 . (canceled)  
     
     
         52 . A method for the modulation of bone adhesion, comprising contacting a cadherin-expressing cell with a modulating agent according to  claim 8 , and thereby modulating bone adhesion.  
     
     
         53 . An implantable medical device or material linked to, coated with or having interspersed within, a cell adhesion modulating agent according to  claim 8 .  
     
     
         54 . The medical device of  claim 53 , wherein the medical device is selected from the group consisting of a balloon, stent, shunt, catheter, stent graft, vascular graft, vascular patch, filter, adventitial wrap, intraluminal paving system, cerebral stent, cerebral aneurysm filter coil, myocardical plug, pacemaker lead, dialysis access graft, and heart valve.