Long lasting fusion peptide inhibitors of viral infection

Abstract

Peptides exhibiting anti-viral and anti-fusogenic activity are modified to provide greater stability and improved half-life in vivo. The selected peptides include fusion inhibitors DP178 and DP107 and related peptides and analogs thereof. The modified peptides are capable of forming covalent bonds with one or more blood components, preferably a mobile blood component.

1 .- 48 . (canceled) 
     
     
         49 . An anti-fusogenic gp41 peptide-albumin conjugate having anti-viral activity against human immunodeficiency virus (HIV), comprising albumin and an anti-fusogenic gp41 peptide that comprises a maleimide containing group and an amino acid sequence, wherein the peptide is covalently bonded to cysteine 34 of the albumin through the maleimide containing group. 
     
     
         50 . The anti-fusogenic gp41 peptide-albumin conjugate of  claim 49 , wherein the albumin is human albumin. 
     
     
         51 . The anti-fusogenic gp41 peptide-albumin conjugate of  claim 49 , wherein the maleimide containing group is maleimidopropionic acid (MPA) or gamma-maleimide-butyralamide (GMBA). 
     
     
         52 . The anti-fusogenic gp41 peptide-albumin conjugate of  claim 49 , wherein the maleimide containing group is attached to the peptide via a linking group. 
     
     
         53 . The anti-fusogenic gp41 peptide-albumin conjugate of  claim 52 , wherein the linking group comprises polyethoxy amino acids. 
     
     
         54 . The anti-fusogenic gp41 peptide-albumin conjugate of  claim 53 , wherein the linking group is (2-amino)ethoxy acetic acid (AEA) or [2-(2-amino)ethoxy)]ethoxy acetic acid (AEEA). 
     
     
         55 . The anti-fusogenic gp41 peptide albumin conjugate of  claim 49 , wherein the maleimide containing group is attached to the peptide without a linking group. 
     
     
         56 . The anti-fusogenic gp41 peptide-albumin conjugate of  claim 49 , wherein the maleimide containing group is attached to the N-terminus of the peptide. 
     
     
         57 . The anti-fusogenic gp41 peptide-albumin conjugate of  claim 49 , wherein the maleimide containing group is attached to a lysine of the peptide. 
     
     
         58 . The anti-fusogenic gp41 peptide albumin conjugate of  claim 49 , wherein the maleimide containing group is attached to the C-terminus of the peptide. 
     
     
         59 . An anti-fusogenic gp41 peptide-human albumin conjugate having anti-viral activity against human immunodeficiency virus (HIV), comprising human albumin and an anti-fusogenic gp41 peptide that comprises an amino acid sequence and a maleimide containing group selected from maleimidopropionic acid (MPA) and gamma-maleimide-butyralamide (GMBA), wherein the maleimide containing group is attached to the N-terminus of the peptide or a lysine residue in the amino acid sequence of the peptide via a linker and the peptide is covalently bonded to cysteine 34 of the albumin through the maleimide containing group. 
     
     
         60 . The anti-fusogenic gp41 peptide-human albumin conjugate of  claim 59 , wherein the linking group comprises polyethoxy amino acids. 
     
     
         61 . The anti-fusogenic gp41 peptide-human albumin conjugate of  claim 60 , wherein the linking group is (2-amino)ethoxy acetic acid (AEA) or [2-(2-amino)ethoxy)]ethoxy acetic acid (AEEA). 
     
     
         62 . A composition comprising the anti-fusogenic peptide-albumin conjugate of  claim 49  and a physiologically acceptable medium. 
     
     
         63 . The composition of  claim 62 , wherein the composition is lyophilized. 
     
     
         64 . The composition of  claim 62 , wherein the composition is formulated for intravenous administration or subcutaneous administration. 
     
     
         65 . A modified anti-fusogenic gp41 peptide having anti-viral activity against human immunodeficiency virus (HIV), comprising an anti-fusogenic gp41 peptide that comprises a maleimide containing group. 
     
     
         66 . The modified anti-fusogenic gp41 peptide of  claim 65 , wherein the maleimide containing group is maleimidopropionic acid (MPA) or gamma-maleimide-butyralamide (GMBA). 
     
     
         67 . The modified anti-fusogenic gp41 peptide of  claim 65 , wherein the maleimide containing group is attached to the peptide via a linking group. 
     
     
         68 . The modified anti-fusogenic gp41 peptide of  claim 67 , wherein the linking group comprises polyethoxy amino acids. 
     
     
         69 . The modified anti-fusogenic gp41 peptide of  claim 68 , wherein the linking group is (2-amino)ethoxy acetic acid (AEA) or [2-(2-amino)ethoxy)]ethoxy acetic acid (AEEA). 
     
     
         70 . The modified anti-fusogenic gp41 peptide of  claim 65 , wherein the maleimide containing group is attached to the peptide without a linking group. 
     
     
         71 . The modified anti-fusogenic gp41 peptide of  claim 65 , wherein the maleimide containing group is attached to the N-terminus of the peptide. 
     
     
         72 . The modified anti-fusogenic gp41 peptide of  claim 65 , wherein the maleimide containing group is attached to a lysine of the peptide. 
     
     
         73 . A method of inhibiting or reducing membrane fusion between human immunodeficiency virus (HIV) and a cell, comprising contacting the HIV virus with an anti-fusogenic gp41 peptide-albumin conjugate of  claim 49 . 
     
     
         74 . A method of making an anti-fusogenic gp41 peptide-albumin conjugate of  claim 49 , comprising:
 contacting a modified anti-fusogenic gp41 peptide of  claim 65  with albumin to form an anti-fusogenic gp41-albumin conjugate.   
     
     
         75 . The method of  claim 74 , wherein the modified anti-fusogenic gp41 peptide is made by combining an anti-fusogenic gp41 peptide having a free amino group, N-[γ-maleimidobutyryloxy]succinimide ester (GMBS) and trietylamine or maleimidopropionic acid (MPA) to form a maleimide containing group at the free amino group, to form the modified anti-fusogenic gp41 peptide. 
     
     
         76 . A method of treating or preventing human immunodeficiency virus (HIV) infection in a subject, comprising
 administering an anti-fusogenic gp41 peptide-albumin conjugate of  claim 49  to a subject having or at risk of HIV, thereby treating or preventing the infection.   
     
     
         77 . The method of  claim 76 , wherein the subject has been subjected to high risk of exposure to HIV.