Compounds and methods for modulating adhesion molecule function

Abstract

Modulating agents and methods for enhancing or inhibiting cadherin-mediated functions are provided. The modulating agents comprise at least an HAV binding motif, an analogue or peptidomimetic thereof, or an antibody or fragment thereof that specifically binds to such a motif. Modulating agents may additionally comprise one or more cell adhesion recognition sequences recognized by cadherins and/or other adhesion molecules. Such modulating agents may, but need not, be linked to a targeting agent, drug and/or support material.

1 . (canceled)  
     
     
         2 . A cell adhesion modulating agent, comprising: 
 (a) an HAV-BM sequence or peptidomimetic thereof;    (b) a polynucleotide encoding an HAV-BM sequence; or    (c) an antibody or antigen-binding fragment thereof that specifically binds to an HAV-BM sequence;    wherein the agent modulates a cadherin-mediated process.    
     
     
         3 . A modulating agent according to  claim 2 , wherein the HAV-BM sequence is: 
 (a) Ile/Val-Phe-Aaa-Ile-Baa-Caa-Daa-Ser/Thr-Gly-Eaa-Leu/Met (SEQ ID NO:3), wherein Aaa, Baa, Caa, Daa and Eaa are independently selected from the group consisting of amino acid residues;    (b) Trp-Leu-Aaa-Ile-Asp/Asn-Baa-Caa-Daa-Gly-Gln-Ile (SEQ ID NO:4), wherein Aaa, Baa, Caa and Daa are independently selected from the group consisting of amino acid residues; or    (c) an analogue of any of the foregoing sequences that retains at least seven consecutive amino acid residues, wherein the ability of the analogue to modulate a cadherin-mediated process is not diminished.    
     
     
         4 . A modulating agent according to  claim 3 , wherein the HAV-BM sequence comprises INPISGQ (SEQ ID NO:22), LNPISGQ (SEQ ID NO:23), IDPVSGQ (SEQ ID NO:24) or IDPVNGQ (SEQ ID NO:94).  
     
     
         5 . A cell adhesion modulating agent according to  claim 3 , wherein the HAV-BM sequence is selected from the group consisting of: IFIINPISGQL (SEQ ID NO:5), IFILNPISGQL (SEQ ID NO:6), VFAVEKETGWL (SEQ ID NO:7), VFSINSMSGRM (SEQ ID NO:8), VFIIERETGWL (SEQ ID NO:9), VFTIEKESGWL (SEQ ID NO:10), VFNIDSMSGRM (SEQ ID NO:11), WLKIDSVNGQI (SEQ ID NO:12), WLKIDPVNGQI (SEQ ID NO:13), WLAMDPDSGQV (SEQ ID NO:14), WLHINATNGQI (SEQ ID NO:15), WLEINPDTGAI (SEQ ID NO:16), WLAVDPDSGQI (SEQ ID NO:17), WLEINPETGAI (SEQ ID NO:18), WLHINTSNGQI (SEQ ID NO:19), NLKIDPVNGQI (SEQ ID NO:20), LKIDPVNGQI (SEQ ID NO:21) and analogues of the foregoing sequences that retain at least seven consecutive residues, wherein the ability of the analogue to modulate a cadherin-mediated process is not diminished.  
     
     
         6 . A modulating agent according to  claim 2 , wherein the HAV-BM sequence comprises at least five consecutive residues of a peptide selected from the group consisting of INPISGQ (SEQ ID NO:22), LNPISGQ (SEQ ID NO:23), NLKIDPVNGQI (SEQ ID NO:20) and WLKIDPVNGQI (SEQ ID NO:13).  
     
     
         7 . A modulating agent according to  claim 6 , wherein the agent comprises a sequence selected from the group consisting of PISGQ (SEQ ID NO:26), PVNGQ (SEQ ID NO:27), PVSGR (SEQ ID NO:28), IDPVN (SEQ ID NO:29), INPIS (SEQ ID NO:30) and KIDPV (SEQ ID NO:31).  
     
     
         8 . A modulating agent according to  claim 2 , wherein the agent comprises an HAV-BM sequence or an analogue thereof present within a peptide ranging in size from 6 to 16 amino acid residues.  
     
     
         9 . A modulating agent according to  claim 2 , wherein the agent comprises an HAV-BM sequence that is present within a linear peptide.  
     
     
         10 . A modulating agent according to  claim 2 , wherein the agent comprises an HAV-BM sequence that is present within a cyclic peptide.  
     
     
         11 .- 23 . (canceled)  
     
     
         24 . A modulating agent according to  claim 2 , wherein the HAV-BM sequence is present within a peptide comprising an N-terminal or C-terminal modification.  
     
     
         25 . A modulating agent according to  claim 2 , wherein the agent comprises an antibody or antigen binding fragment thereof that binds to an HAV-BM sequence.  
     
     
         26 .- 38 . (canceled)  
     
     
         39 . A method for modulating a cadherin-mediated function, comprising contacting a cadherin-expressing cell with a cell adhesion modulating agent according to  claim 2 .  
     
     
         40 .- 62 . (canceled)