Protease inhibition

Abstract

The invention relates to a method for inhibiting an adam protease, comprising inhibiting binding to an integrin-binding loop of a disintegrin domain in the adam protease. Also provided are cyclic peptides which inhibit binding to an integrin-binding loop of an adam protease, as well as associated pharmaceutical compositions, uses and methods of treatment.

1 . A cyclic peptide of formula I: 
       
         
           
           
               
               
           
         
         wherein X 0 , X 1 , X 2  and X 3  each independently represents an amino acid residue, each amino acid residue in the ring being joined by a peptide bond; 
         the sequence X 1 —X 2 —X 3  is present in an integrin-binding loop of a disintegrin domain of an ADAM protease; 
         and n is 0 to 4; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A cyclic peptide according to  claim 1 , wherein the cyclic peptide has the formula II: 
       
         
           
           
               
               
           
         
         wherein α 0 , α 1 , α 2  and α 3  each independently represents an alpha-amino acid residue; 
         β represents a beta-amino acid residue; 
         each amino acid residue in the ring is joined by a peptide bond; 
         m is 1 to 3; and 
         at least the amino acid sequence α 1 -α 2 -α 3  is present in an integrin-binding loop of a disintegrin domain of an ADAM protease; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . A cyclic peptide according to  claim 2 , wherein the cyclic peptide has the formula III: 
       
         
           
           
               
               
           
         
         wherein R α0 , R α1 , R α2  and R α3  each independently represents an alpha-amino acid side-chain; 
         R β  represents a beta-amino acid side-chain; 
         p is 1 to 3; and 
         R α2  and R α3  are selected such that the cyclic peptide comprises a 3 amino acid sequence present in an integrin-binding loop of a disintegrin domain of an ADAM protease; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . A cyclic peptide according to  claim 1 , wherein (i) X 1 , X 2  and X 3  (ii) α 1 , α 2  and α 3  or (iii) R α1 , R α2  and R α3  are selected such that the cyclic peptide comprises one of the following amino acid sequences: KDK, KDM, TSE, KDE, SNS. ARQ, MGD, DSD, ROD, NAT, VRQ, ATD & TDD. 
     
     
         5 . A cyclic peptide according to  claim 4 , wherein the cyclic peptide comprises a sequence KDK or KDM. 
     
     
         6 . A cyclic peptide according to  claim 1 , wherein (i) n, X 0 , X 1 , X 2  and X 3  (ii) m, α 0 , α 1 , α 2  and α 3  or (iii) p, R α0 , R α1 , R α2  and R α3  are selected such that the cyclic peptide comprises one of the following amino acid sequences: RLSKDK, RPKKDM, RGKTSE, RPAKDE, RPTRGD, RDSSNS, REQARQ, RQAMGD, RDDSD, QEAINAT, RAAKDE, RGSSNS, REQVRQ, RPAATD, & RPPTDD. 
     
     
         7 . A cyclic peptide according to  claim 6 , wherein the cyclic peptide comprises a sequence RLSKDK or RPKKDM. 
     
     
         8 . A cyclic peptide according to  claim 1 , which is cyclo(RLsKDK), cyclo(RGkTSE), cyclo(RPaKDE), cyclo(RPkKDM), cyclo(RPtRGD), cyclo(RDsSNS), cyclo(REqARQ), cyclo(RQaMGD), cyclo(RdDSD), cyclo(QEAiNAT), cyclo(RAaKDE), cyclo(RGsSNS), cyclo(REqVRQ), cyclo(RPaATD) or cyclo(RPpTDD), wherein a lower case letter represents a beta amino acid and an upper case letter represents an alpha amino acid, or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A cyclic peptide according to  claim 8 , which is cyclo(Arg-Pro-{β-Lys}-Lys-Asp-Met) or cyclo(Arg-Leu-{β-Ser}-Lys-Asp-Lys) or a pharmaceutically acceptable salt thereof. 
     
     
         10 . A cyclic peptide according to  claim 1 , which inhibits binding to an integrin-binding loop of a disintegrin domain in an ADAM protease. 
     
     
         11 . A pharmaceutical composition comprising a cyclic peptide as set out in  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         12 . A pharmaceutical composition as set out in  claim 11  for use in treating a disease or condition associated with ADAM protease activity. 
     
     
         13 . A method for treating a subject suffering from a condition associated with ADAM protease activity, comprising administering to the subject a therapeutically effective amount of a cyclic peptide as set out in  claim 1 . 
     
     
         14 . The method according to  claim 13 , wherein the disease or condition comprises cancer, an inflammatory condition or allergy. 
     
     
         15 . A method for inhibiting an ADAM protease, comprising inhibiting binding to an integrin-binding loop of a disintegrin domain in the ADAM protease. 
     
     
         16 . A method according to  claim 15 , wherein inhibiting binding comprises contacting the ADAM protease with an agent which binds to the integrin-binding loop of the disintegrin domain. 
     
     
         17 . A method according to  claim 16 , wherein the agent comprises an antibody or antibody fragment. 
     
     
         18 . A method according to  claim 15 , wherein inhibiting binding comprises contacting the ADAM protease with an agent which mimics the structure of the integrin-binding loop. 
     
     
         19 . A method according to  claim 18 , wherein the agent comprises a peptide comprising an amino acid sequence present in the integrin-binding loop. 
     
     
         20 . A method according to  claim 19 , wherein the peptide comprises a cyclic peptide. 
     
     
         21 . A method according to  claim 19 , wherein the peptide is 5 to 7 amino acid residues in length. 
     
     
         22 . A method according to  claim 19 , wherein the peptide comprises at least a 3 amino acid sequence present in the integrin-binding loop of the disintegrin domain of the ADAM protease at a location corresponding to that of an RGD sequence in snake venom disintegrins and/or ADAM15. 
     
     
         23 . A method according to  claim 19 , wherein the peptide comprises one or more beta-amino acid residues. 
     
     
         24 . A method according to  claim 15 , wherein the ADAM protease comprises ADAMS, ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, ADAM19, ADAM28 or ADAM33.