Compstatin analogs with improved activity

Abstract

Compounds comprising peptides and peptidomimetics capable of binding the C3 protein and inhibiting complement activation are disclosed. These compounds display improved complement activation-inhibitory activity as compared with currently available compounds. Isolated nucleic acid molecules encoding the peptides are also disclosed.

What is claimed: 
     
         1 . A compound that inhibits complement activation, which comprises a peptide having a sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 15) 
                 
                     
                   Xaa1-Cys-Val-Xaa2-Gln-Asp-Trp-Gly-Xaa3-His- 
                 
                     
                     
                 
                     
                   Arg-Cys-Xaa4; 
                 
             
                
                
                
                
               
            
           
         
         wherein: 
         Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile; 
         Xaa2 is Tip or a peptidic or non-peptidic analog of Trp; 
         Xaa3 is His, Ala, Phe or Trp; 
         Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly or Asn optionally is replaced by —NH 2 ; and 
         the two Cys residues are joined by a disulfide bond. 
       
     
     
         2 . The compound of  claim 1 , wherein Xaa1 is Ac-Ile. 
     
     
         3 . The compound of  claim 1 , wherein Xaa3 is Ala. 
     
     
         4 . The compound of  claim 1 , wherein Xaa2 is an analog of Trp comprising a substituted or unsubstituted bicyclic aromatic ring component or two or more substituted or unsubstituted monocyclic aromatic ring components. 
     
     
         5 . The compound of  claim 4 , wherein the analog of Trp is selected from the group consisting of 2-napthylalanine, 1-naphthylalanine, 2-indanylglycine carboxylic acid, dihydrotryptophan and benzoylphenylalanine 
     
     
         6 . The compound of  claim 1 , wherein Xaa1 is Ac-Ile, Xaa2 is Trp or an analog of Trp comprising a substituted or unsubstituted indole, naphthyl or dibenzoyl component, Xaa3 is Ala and Xaa4 is L-threonine or D-threonine. 
     
     
         7 . The compound of  claim 6 , having a sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13. 
     
     
         8 . The compound of  claim 1 , wherein Xaa1 is a dipeptide Gly-Ile, and Xaa 4 is a tripeptide Thr-Ala-Asn. 
     
     
         9 . The compound of  claim 8 , comprising a peptide having SEQ ID NO:14. 
     
     
         10 . A compound that inhibits complement activation, comprising a non-peptide or partial peptide mimetic of the compound of  claim 1 , wherein the compound binds C3 and inhibits complement activation with at least five-fold greater activity than does a peptide comprising SEQ ID NO:1, under equivalent assay conditions. 
     
     
         11 . An isolated nucleic acid molecule encoding one or more peptides that inhibits complement activation, wherein the peptide comprises a sequence:
 Xaa1-Cys-Val-Xaa2-Gln-Asp-Trp-Gly-Xaa3-His-Arg-Cys-Xaa4 (SEQ ID NO:15);   wherein:   Xaa1 is Ile, Val, Leu, or a dipeptide comprising Gly-Ile;   Xaa2 is Trp;   Xaa3 is His, Ala, Phe or Trp; and   Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, or a tripeptide comprising Thr-Ala-Asn;   wherein the two Cys residues are joined by a disulfide bond.   
     
     
         12 . The isolated nucleic acid molecule of  claim 11 , encoding a peptide wherein Xaa3 is Ala. 
     
     
         13 . The isolated nucleic acid molecule of  claim 12 , encoding a peptide comprising SEQ ID NO:14. 
     
     
         14 . The isolated nucleic acid molecule of  claim 13 , encoding a concatemer of two or more of a peptide comprising SEQ ID NO:14, wherein the encoded concatemer is cleavable by hydrazine to form a multiplicity of peptides comprising SEQ ID NO:14. 
     
     
         15 . An expression vector comprising the isolated nucleic acid molecule of  claim 11 . 
     
     
         16 . A cell comprising the expression vector of  claim 15 . 
     
     
         17 . The cell of  claim 16 , which is a bacterial, fungal, plant, insect or mammalian cell.