Inhibitors of hiv replication and method of treatment of hiv infections

Abstract

The invention is drawn to a novel class of drugs directed against HIV, comprising a peptide or analog comprising a decapeptide, said decapeptide containing (from N-terminus to the C-terminus) a basic amino acid in position 1, an acidic amino acid in positions 2 and 5, and a tryptophan in positions 4, 7, and 8, and to a method of treatment of HIV infections, in particular multidrug-resistant HIV infections.

1 . A method for treating or inhibiting an HIV infection, comprising administering to a human in need thereof a therapeutically effective amount of an inhibitor of HIV replication, wherein:
 the inhibitor of HIV replication comprises an antiviral peptide;   the antiviral peptide consists of a decapeptide containing (from the N-terminus to the C-terminus) a basic amino acid at position 1; an acidic amino acid at positions 2 and 5; a tryptophan at positions 4, 7, and 8; a threonine, isoleucine or valine at position 3; a threonine, alanine, or glutamine at position 6; a threonine, alanine, valine, isoleucine, methionine, or aspartate at position 9; and a glutamate, aspartate or asparagine at position 10; and   the decapeptide inhibits the dimerization of HIV reverse transcriptase.   
     
     
         2 . The method of  claim 1 , wherein the basic amino acid at position 1 is lysine or arginine. 
     
     
         3 . The method of  claim 1 , wherein the acidic amino acid at position 2 is glutamate. 
     
     
         4 . The method of  claim 1 , wherein the amino acid at position 5 is glutamate. 
     
     
         5 . The method of  claim 1 , wherein the decapeptide is selected from the group consisting of KETWETWWTE (SEQ ID NO:1), KETWATWWTE (SEQ ID NO:22), and KEAWETWWTE (SEQ ID NO:23). 
     
     
         6 . The method of  claim 1 , wherein the decapeptide is not KETWETWWTE (SEQ ID NO: 1). 
     
     
         7 . The method of  claim 1 , wherein the inhibitor of HIV replication further comprises a pharmaceutically acceptable excipient. 
     
     
         8 . The method of  claim 1 , wherein the inhibitor of HIV replication further comprises a vector that allows penetration of the antiviral peptide into a mammalian cell. 
     
     
         9 . The method of  claim 8 , wherein the vector is selected from the group consisting of a liposome, a polymeric protein-binding cation, a protein, a peptide, a microparticle, and a nanoparticle. 
     
     
         10 . The method of  claim 9 , wherein the vector is a peptide. 
     
     
         11 . The method of  claim 10 , wherein the peptide is an MPG peptidyl carrier. 
     
     
         12 . The method of  claim 11 , wherein the MPG peptidyl carrier comprises SEQ ID NO:2 or SEQ ID NO:3. 
     
     
         13 . The method of  claim 11 , wherein the MPG peptidyl carrier and the antiviral peptide are in the form of a complex. 
     
     
         14 . The method of  claim 13 , wherein the complex comprises the MPG peptidyl carrier and the antiviral peptide at a ratio of about 20 molecules of the MPG peptidyl carrier for 1 molecule of the antiviral peptide. 
     
     
         15 . A method for treating or inhibiting an HIV infection, comprising administering to a human in need thereof a therapeutically effective amount of an inhibitor of HIV replication, wherein:
 the inhibitor of HIV replication comprises a chimeric peptide; and   the chimeric peptide comprises:   (a) a decapeptide containing (from the N-terminus to the C-terminus) a basic amino acid at position 1; an acidic amino acid at positions 2 and 5; a tryptophan at positions 4, 7, and 8; a threonine, isoleucine or valine at position 3; a threonine, alanine, or glutamine at position 6; a threonine, alanine, valine, isoleucine, methionine, or aspartate at position 9; and a glutamate, aspartate or asparagine at position 10; wherein the decapeptide inhibits the dimerization of HIV reverse transcriptase, and   (b) an MPG peptidyl carrier peptide.   
     
     
         16 . The method of  claim 15 , wherein the basic amino acid at position 1 is lysine or arginine. 
     
     
         17 . The method of  claim 15 , wherein the acidic amino acid at position 2 is glutamate. 
     
     
         18 . The method of  claim 15 , wherein the amino acid at position 5 is glutamate. 
     
     
         19 . The method of  claim 15 , wherein the inhibitor of HIV replication further comprises a pharmaceutically acceptable excipient. 
     
     
         20 . The method of  claim 15 , wherein the MPG peptidyl carrier peptide is SEQ ID NO:2 or SEQ ID NO:3. 
     
     
         21 . The method of  claim 15 , wherein the decapeptide is selected from the group consisting of KETWETWWTE (SEQ ID NO:1), KETWATWWTE (SEQ ID NO:22), and KEAWETWWTE (SEQ ID NO:23) 
     
     
         22 . The method of  claim 15 , wherein the chimeric peptide is SEQ ID NO:4. 
     
     
         23 . The method of  claim 15 , wherein the chimeric peptide is SEQ ID NO:6. 
     
     
         24 . The method of  claim 1 , wherein the method further comprises administering one or more additional anti-HIV medicaments. 
     
     
         25 . The method of  claim 15 , wherein the method further comprises administering one or more additional anti-HIV medicaments.