Peptides

Abstract

An internally-constrained cyclic oligopeptide comprising a ring of at least six amino acids for specifically binding to a target ligand, wherein the ring comprises a plurality of amino acid domains, each domain comprising at least two epitope-forming amino acids, and two or more associating functional groups positioned so that they form one or more intra-cyclic associations; whereby the cyclic oligopeptide is constrained in a single conformation so that the epitope-forming amino acids form an epitope in each domain, each epitope being capable of specifically binding to a target ligand.

1 . An internally-constrained cyclic oligopeptide comprising a ring of at least six amino acids for specifically binding to a target ligand, wherein the ring comprises a plurality of amino acid domains, each domain comprising at least two epitope-forming amino acids, and two or more associating functional groups positioned so that they form one or more intra-cyclic associations; whereby the cyclic oligopeptide is constrained in a single conformation so that the epitope-forming amino acids form an epitope in each domain, each epitope being capable of specifically binding to a target ligand. 
     
     
         2 . The cyclic oligopeptide according to  claim 1 , wherein each domain comprises three epitope-forming amino acids and the three epitope-forming amino acids have alternating stereochemical configurations. 
     
     
         3 . The cyclic oligopeptide according to  claim 1 , wherein the amino acids are naturally occurring amino acids, amino acid analogues or D-forms thereof. 
     
     
         4 . The cyclic oligopeptide according to  claim 1 , wherein the one or more intra-cyclic associations between the associating functional groups are non-covalent. 
     
     
         5 . The cyclic oligopeptide according to  claim 4 , wherein the one or more intra-cyclic associations between the associating functional groups are hydrophobic. 
     
     
         6 . The cyclic oligopeptide according to  claim 1 , wherein at least one associating functional group is positioned between the domains. 
     
     
         7 . The cyclic oligopeptide according to  claim 6 , wherein each epitope-forming amino acid adjacent to an associating functional group has the same stereochemical configuration as the adjacent associating functional group. 
     
     
         8 . The cyclic oligopeptide according to  claim 1 , wherein the epitopes are the same. 
     
     
         9 . The cyclic oligopeptide according  claim 1 , wherein the associating functional groups are borne on associating amino acids. 
     
     
         10 . The cyclic oligopeptide according to  claim 1 , wherein the associating amino acids are lipidic amino acids. 
     
     
         11 . The cyclic oligopeptide according to  claim 10 , wherein at least one of the associating functional groups borne on the lipidic amino acids is a C 8 -C 20  linear hydrocarbon side chain. 
     
     
         12 . The cyclic oligopeptide according to  claim 10 , wherein the linear hydrocarbon side chain is a C 10 -C 16  linear hydrocarbon side chain. 
     
     
         13 . The cyclic oligopeptide according to  claim 1 , which has the following structure: 
       
         
           
           
               
               
           
         
         wherein A, B, C, X, Y and Z represent the epitope-forming amino acids; A and X represent D amino acids and B, C, Y and Z represent L amino acids or A and X represent L amino acids and B, C, Y and Z represent D amino acids; one epitope is formed from the domain C-A-B and one epitope is formed from the domain Z—X—Y; and each Σ represents an associating amino acid. 
       
     
     
         14 . The cyclic oligopeptide according to  claim 13 , wherein the Z—X—Y domain and/or the C-A-B domain is selected from the amino acid sequences RFS, RSF, FSR, FRS, SRF, SFR, QLS, QSL, SQL, SLQ, LQS or LSQ and each Σ is a lipidic amino acid with a linear hydrocarbon side chain associating functional group comprising a hydrocarbon chain between 8 and 20 carbons in length. 
     
     
         15 . The cyclic oligopeptide according to  claim 14 , wherein the Z—X—Y domain and/or the C-A-B domain form an epitope capable of suppressing TNF secretion. 
     
     
         16 . The cyclic oligopeptide according to  claim 14 , wherein the Z—X—Y domain is RFS. 
     
     
         17 . The cyclic oligopeptide according to  claim 16 , wherein phenylalanine is of D configuration, serine is of L configuration, arginine is of L configuration and each lipidic amino acid is of L configuration. 
     
     
         18 . The cyclic oligopeptide according to  claim 13 , wherein the domain C-A-B is the same as the domain Z—X—Y. 
     
     
         19 . The cyclic oligopeptide according to  claim 1 , wherein the cyclic oligopeptide comprises two domains and an epitope is formed from the three epitope-forming amino acids in each domain. 
     
     
         20 . The cyclic oligopeptide according to  claim 19 , wherein the oligopeptide comprises two associating functional groups. 
     
     
         21 . A medicament, prophylactic, or diagnostic comprising the cyclic oligopeptide according to  claim 1 . 
     
     
         22 . A pharmaceutical composition comprising the cyclic oligopeptide according to  claim 1  and a pharmaceutically acceptable excipient and/or adjuvant. 
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein the excipient is selected from the group consisting of transcutol, poloxamer block-copolymers, cyclodextrins, non-ionic surfactants, and bile salts. 
     
     
         24 . The pharmaceutical composition according to  claim 22 , wherein the non-ionic surfactants are selected from the group consisting of acyl esters of polyethylene glycol and aliphatic ethers of polyethylene glycol. 
     
     
         25 . A method for producing the cyclic oligopeptide of  claim 1  for specifically binding to a target ligand comprising:
 i) providing the epitope-forming amino acids; 
 ii) producing a cyclic oligopeptide incorporating the epitope-forming amino acids. 
 
     
     
         26 . The method according to  claim 25 , wherein the step of providing the epitope-forming amino acids comprises
 (a) selecting a set of conjugates, each conjugate comprising a head group and a tail group, with an array of head groups, wherein each head group comprises an amino acid;   (b) forming a non-covalent association therefrom, in which the tail groups aggregate hydrophobically and in which the conjugates are movable;   (c) assaying for sufficient interaction between the noncovalent association and the target ligand;   (d) optionally repeating steps (a) to (c) using a set of conjugates with a modified array of head groups; and   (e) on finding sufficient interaction in step (c) selecting the amino acids of the head groups of the set of conjugates as the epitope-forming amino acids in step (a).