Compstatin Analogs for Treatment of Neuropathic Pain

Abstract

In some aspects, the present invention provides methods of treating a subject in need of treatment for neuropathic pain, the method comprising administering a compstatin analog to the subject. In some embodiments, the compstatin analog is administered parenterally, e.g., intravenously.

We claim: 
     
         1 . A method of treating a subject in need of treatment for neuropathic pain, the method comprising administering a compstatin analog to the subject. 
     
     
         2 . The method of  claim 1 , wherein the compstatin analog is administered intravenously. 
     
     
         3 . The method of  claim 1 , wherein the activity of the compstatin analog is at least 100 times as great as the activity of compstatin as measured in an in vitro assay. 
     
     
         4 . The method of  claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′aa-Gln-Asp-Xaa-Gly (SEQ ID NO: 3), where X′aa and Xaa are selected from Trp and analogs of Trp. 
     
     
         5 . The method of  claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′aa-Gln-Asp-Xaa-Gly-X″aa (SEQ ID NO: 4), where X′aa and Xaa are each independently selected from Trp and analogs of Trp and X″aa is selected from His, Ala, single methyl unbranched amino acids, Phe, Trp, and analogs of Trp. 
     
     
         6 . The method of  claim 5 , wherein the peptide has a sequence of X′aa1-X′aa2-X′aa3-X′aa-Gln-Asp-Xaa-Gly-X″aa-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), and X′aa1, X′aa2, X′aa3, X″aa2, X″aa3-X″aa4, and X″aa5 are identical to the amino acids at the corresponding positions in compstatin. 
     
     
         7 . The method of  claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence of X′aa1-X′aa2-X′aa3-X′aa4-Gln-Asp-Xaa-Gly-X″aa1-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), where X′aa4 and Xaa are selected from Trp and analogs of Trp, wherein X′aa1, X′aa2, X′aa3, X″aa1, X″aa2, X″aa3, X″aa4, and X″aa5 are independently selected from among amino acids and amino acid analogs, and the peptide is cyclized via a bond between X′aa2 and X″aa4. 
     
     
         8 . The method of  claim 7 , wherein X′aa1, X′aa2, X′aa3, X″aa2, X″aa3, X″aa4, and X″aa5 are identical to the amino acids at the corresponding positions in compstatin and X″aa1 is Ala or a single methyl unbranched amino acid. 
     
     
         9 . The method of  claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence: 
       
         
           
                 
               
                   (SEQ ID NO: 6) 
                 
                   Xaa1-Cys-Val-Xaa2-Gln-Asp-Xaa2*-Gly*-Xaa3-His-Arg- 
                 
                   Cys-Xaa4; 
                 
             
                
                
                
               
            
           
         
       
       wherein:
 Xaa1 is Ile, Val, Leu, B 1 -Ile, B 1 -Val, B 1 -Leu or a dipeptide comprising Gly-Ile or B 1 -Gly-Ile, and B 1  represents a first blocking moiety; 
 Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp; 
 Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp; 
 Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by a second blocking moiety B 2 ; and 
 the two Cys residues are joined by a disulfide bond. 
 
     
     
         10 . The method of  claim 9 , wherein
 Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile or Ac-Gly-Ile;
 Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp; 
 Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp; 
 Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by —NH 2 . 
   
     
     
         11 . The method of  claim 9 , wherein Xaa2 is an analog of Trp having increased hydrophobic character relative to Trp. 
     
     
         12 . The method of  claim 9 , 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. 
     
     
         13 . The method of  claim 9 , wherein Xaa2* is an analog of Trp having an electronegative substituent on the indole ring and not having increased hydrophobic character relative to Trp. 
     
     
         14 . The method of  claim 9 , wherein the compstatin analog has a sequence selected from the group consisting of: SEQ ID NOs: 9-36 
     
     
         15 . The method of  claim 9 , wherein the compstatin analog has a sequence selected from the group consisting of: SEQ ID NOs: 14, 21, 28, 29, 32, 33, 34, or 36. 
     
     
         16 . The method of  claim 9 , wherein the compstatin analog has the sequence of SEQ ID NO: 28, 32, or 34. 
     
     
         17 . The method of  claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence of X′aa1-X′aa2-X′aa3-X′aa4-Gln-Asp-Xaa-Gly-X″aa1-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), where X′aa4 and Xaa are selected from Trp and analogs of Trp, wherein X′aa1, X′aa2, X′aa3, X″aa1, X″aa2, X″aa3, X″aa4, and X″aa5 are independently selected from among amino acids and amino acid analogs, X′aa2 and X″aa4 are not Cys, and the peptide is cyclized via a bond between X′aa2 and X″aa4. 
     
     
         18 . The method of  claim 17 , wherein X′aa1, X′aa3, X″aa2, X″aa3, and X″aa5 are identical to the amino acids at the corresponding positions in compstatin and X″aa1 is Ala or a single methyl unbranched amino acid. 
     
     
         19 . The method of  claim 17 , wherein the bond is an amide bond, wherein one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a primary or secondary amine, the other one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a carboxylic acid group, and the bond is an amide bond. 
     
     
         20 . The method of  claim 1 , wherein the peptide is acetylated at the N-terminus, amidated at the C-terminus, or both acetylated at the N-terminus and amidated at the C-terminus. 
     
     
         21 . The method of  claim 1 , further comprising: administering a conventional treatment for neuropathic pain to the subject.