Hiv fusion inhibitor peptides with improved biological properties

Abstract

Provided is an HIV fusion inhibitor peptide having an amino acid sequence of any one of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, or SEQ ID NO:15; and provided is a pharmaceutical composition comprising a HIV fusion inhibitor peptide and one or more of a pharmaceutically acceptable carrier and macromolecular carrier, and uses and methods of treatment provided by these compositions.

What is claimed is: 
     
         1 . An isolated peptide comprising an amino acid sequence consisting of any one of the following: SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15. 
     
     
         2 . The peptide of  claim 1 , further comprising a component selected from the group consisting of one or more reactive functionalities, a pharmaceutically acceptable carrier, a macromolecular carrier, and a combination thereof. 
     
     
         3 . The peptide of  claim 1 , wherein the peptide is up to 60 amino acids in length. 
     
     
         4 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding a peptide according to  claim 1 . 
     
     
         5 . A vector comprising the nucleic acid molecule of  claim 4 . 
     
     
         6 . The vector of  claim 5 , wherein the vector is an expression vector. 
     
     
         7 . An isolated cell comprising the vector of  claim 5  or  6 . 
     
     
         8 . A composition comprising the peptide of  claim 2 . 
     
     
         9 . The composition of  claim 2 , wherein the composition is sterile. 
     
     
         10 . A therapeutic regimen comprising a combination of antiviral agents for treatment of HIV-1, the combination comprising the peptide of  claim 1  and one of more antiviral agents selected from the group consisting of an HIV entry inhibitor, HIV integrase inhibitor, reverse transcriptase inhibitor, protease inhibitor, vif-inhibitor, viral-specific transcription inhibitor, viral processing inhibitor, HIV maturation inhibitor, and a combination thereof. 
     
     
         11 . A method of inhibition of transmission of HIV to a cell, comprising contacting the virus, in the presence of a cell, with an amount of the peptide of  claim 1  effective to inhibit infection of the cell by HIV. 
     
     
         12 . A method for inhibiting HIV fusion, comprising contacting the virus, in the presence of a cell, with an amount of the peptide of  claim 1  effective to inhibit HIV fusion. 
     
     
         13 . A method for treating an HIV-infected individual, comprising administering to the individual an amount of the peptide of  claim 1  effective to achieve, in the treated individual, a therapeutic result selected from the group consisting of a reduction in the HIV viral load, an increase in circulating CD4 ± cell population, and a combination thereof. 
     
     
         14 . A method of synthesizing the peptide of SEQ ID NO:9, wherein a set of three peptide fragments are produced by solid and solution phase synthesis, the set comprising:
 (a) SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, and a leucine residue;   or (b) SEQ ID NO:17, SEQ ID NO:18 and SEQ ID NO:20;   
       wherein the members of the set are then combined using a fragment condensation approach to produce the SEQ ID NO:9 peptide. 
     
     
         15 . A set of peptides, wherein the set comprises: 
       
         
           
                 
                 
               
                   (a) 
                     
                 
                   TTWEAWDRAIAE, 
                   (SEQ ID NO: 17) 
                 
                     
                 
                   YAARIEALLRALQE, 
                   (SEQ ID NO: 18) 
                 
                     
                 
                   QQEKNEAALRE; 
                   (SEQ ID NO: 19) 
                 
                     
                 
                   (b) 
                     
                 
                   TTWEAWDRAIAE, 
                   (SEQ ID NO: 17) 
                 
                     
                 
                   YAARIEALLRALQE, 
                   (SEQ ID NO: 18) 
                 
                     
                 
                   QQEKNEAALREL; 
                   (SEQ ID NO: 20) 
                 
                     
                 
                   (c) 
                     
                 
                   TTWEAWDRAIAEYAARIEAL, 
                   (SEQ ID NO: 29) 
                 
                     
                 
                   LRALQEQQEKNEAALRE; 
                   (SEQ ID NO: 30) 
                 
                     
                 
                   (d) 
                     
                 
                   TTWEAWDRAIAEYAARIEAL, 
                   (SEQ ID NO: 29) 
                 
                     
                 
                   LRALQEQQEKNEAALREL; 
                   (SEQ ID NO: 31) 
                 
                     
                 
                   (e) 
                     
                 
                   TTWEAWDRAIA, 
                   (SEQ ID NO: 21) 
                 
                     
                 
                   EYAARIEALLRALQE, 
                   (SEQ ID NO: 22) 
                 
                     
                 
                   QQEKNEAALRE; 
                   (SEQ ID NO: 19) 
                 
                     
                 
                   (f) 
                     
                 
                   TTWEAWDRAI, 
                   (SEQ ID NO: 23) 
                 
                     
                 
                   AEYAARIEALLRALQE, 
                   (SEQ ID NO: 24) 
                 
                     
                 
                   QQEKNEAALRE; 
                   (SEQ ID NO: 19) 
                 
                     
                 
                   (g) 
                     
                 
                   TTWEAWDRA, 
                   (SEQ ID NO: 25) 
                 
                     
                 
                   IAEYAARIEALLRALQE, 
                   (SEQ ID NO: 26) 
                 
                     
                 
                   QQEKNEAALRE; 
                   (SEQ ID NO:19) 
                 
                     
                 
                   (h) 
                     
                 
                   TTWEAWDR, 
                   (SEQ ID NO: 27) 
                 
                     
                 
                   AIAEYAARIEALLRALQE, 
                   (SEQ ID NO: 28) 
                 
                     
                 
                   QQEKNEAALRE; 
                   (SEQ ID NO: 19) 
                 
                     
                 
                   (i) 
                     
                 
                   TTWEAWDRAIA, 
                   (SEQ ID NO: 21) 
                 
                     
                 
                   EYAARIEALLRALQE, 
                   (SEQ ID NO: 22) 
                 
                     
                 
                   QQEKNEAALREL; 
                   (SEQ ID NO: 20) 
                 
                     
                 
                   (j) 
                     
                 
                   TTWEAWDRAI, 
                   (SEQ ID NO: 23) 
                 
                     
                 
                   AEYAARIEALLRALQE, 
                   (SEQ ID NO: 24) 
                 
                     
                 
                   QQEKNEAALREL; 
                   (SEQ ID NO: 20) 
                 
                     
                 
                   (k) 
                     
                 
                   TTWEAWDRA, 
                   (SEQ ID NO: 25) 
                 
                     
                 
                   IAEYAARIEALLRALQE, 
                   (SEQ ID NO: 26) 
                 
                     
                 
                   QQEKNEAALREL; 
                   (SEQ ID NO: 20) 
                 
                     
                 
                   (l) 
                     
                 
                   TTWEAWDR, 
                   (SEQ ID NO: 27) 
                 
                     
                 
                   AIAEYAARIEALLRALQE, 
                   (SEQ ID NO: 28) 
                 
                     
                 
                   QQEKNEAALREL; 
                   (SEQ ID NO: 20) 
                 
                     
                 
                   (m) 
                     
                 
                   TTWEAWDRAIAEYAARIE, 
                   (SEQ ID NO: 32) 
                 
                     
                 
                   ALLRALQEQQEKNEAALRE; 
                   (SEQ ID NO: 33) 
                 
                     
                 
                   (n) 
                     
                 
                   TTWEAWDRAIAEYAARIE, 
                   (SEQ ID NO: 32) 
                 
                     
                 
                   ALLRALQEQQEKNEAALREL; 
                   (SEQ ID NO: 34) 
                 
                     
                 
                   (o) 
                     
                 
                   TTWEAWDRAIAEYAARIEALLRALQE, 
                   (SEQ ID NO: 40) 
                 
                     
                 
                   QQEKNEAALRE; 
                   (SEQ ID NO: 19) 
                 
                   or 
                     
                 
                     
                 
                   (p) 
                     
                 
                   TTWEAWDRAIAEYAARIEALLRALQE, 
                   (SEQ ID NO: 40), 
                 
                     
                 
                   QQEKNEAALREL. 
                   (SEQ ID NO: 20) 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         16 . The set of peptides of  claim 15 , wherein one or more side chains of at least one peptide is protected with a protecting group. 
     
     
         17 . The set of peptides of  claim 16 , wherein the protecting group is selected from the group consisting of 9-fluoroenylmethoxy-carbonyl (Fmoc), t-butyl (t-Bu), trityl (trt), t-butyloxycarbonyl (Boc), carbobenzoxyl, dansyl and a para-nitrobenzyl ester group.