An albumin-conjugated peptide exhibits potent anti-HIV activity and long in vivo half-life

Abstract

The clinical application of conventional peptide drugs often is limited by their short in vivo half-life and potential immunogenicity. Frequent injection presents challenges to the treatment of chronic diseases, such as HIV infection. We chemically modified a peptide HIV fusion inhibitor with 3-maleimidopropionic acid (MPA), which allows rapid and irreversible conjugation with serum albumin at a 1:1 molar ratio. FB006M, with an MPA modification at the 13th amino acid, rapidly formed conjugate with albumin upon intravenous injection, and it exhibited a remarkably extended in vivo half-life. The albumin conjugate of FB006M displayed potent inhibitory activity against a number of laboratory and clinical isolates of HIV-1 in vitro and in vivo. No immunogenicity or antibody formation was detected after repeated dosing. The clinical application of FB006M may decrease the cost of treatment and improve treatment compliance and patient quality of life.

FIG. 1.

(A) Aligned sequences of C34, enfuvirtide, and FB006. The boldface and underlined letters in the FB006 sequence are the residues that differ from those in C34. The amino termini of all peptides were acetylated, and the carboxyl termini were amidated. (B) Structure of FB006M.

FIG. 2.

In vivo albumin binding in rats. FB006M was injected intravenously in two male Sprague-Dawley rats at 63.0 mg/kg. Serial blood samples were collected from each animal at predose (before injection) and at 1, 2, 6, and 10 h after injection. The plasma samples were analyzed by LC-MS. Data from the two animals are very similar. Data for animal 1 are shown.

FIG. 3.

Plasma concentration of FB006M and FB006 following single intravenous administration. (A) The compounds were administered at 4.8 mg/kg. Each time point is represented by the mean values and standard deviations for five male Sprague-Dawley rats. (B) FB006 and FB006M were administered individually at 5.0 mg/kg in one male rhesus monkey. The concentrations were determined by a validated ELISA using rabbit polyclonal antibodies against FB006. Solid circle, FB006; open circle, FB006M.