Enhanced HIV Fusion Inhibitors Efficacy Requires Membrane Affinity and Exposure of the Pocket Binding Domain of C34 Derivatives

Abstract

Viral fusion inhibitors block the fusion between the membranes of an enveloped virus and a target cell, therefore preventing the entry of the viral content. It has been demonstrated that the combination of cholesterol-tagging and dimerization of the C34 peptide sequence resulted both in an increase of the antiviral potency and extension of the in vivo half-life of two new HIV fusion inhibitors: HIVP3 (C34-PEG4-cholesterol) and HIVP4 ([C34-PEG4]2-cholesterol). Given the importance of lipophilicity and selective affinity for different lipid domains, the aim was to evaluate the interaction of these HIV fusion inhibitor peptides with biomembranes model systems and human blood cells, in order to clarify where and how they are located. This study allowed the understanding of the mechanism of action of these peptides at the molecular level, and which strategies may be followed to increase their fusion inhibition efficacy. Membrane partition, dipole potential and surface pressure measurements indicated that HIVP3 and HIVP4 interact preferentially with cholesterol-rich liquid ordered membranes. HIVP3 and HIVP4 are able to interact with human erythrocytes and peripheral blood mononuclear cells to a similar degree as previously described for the simpler drug C34-cholesterol. However, the pocket binding domain(PBD) of both HIVP3 and HIVP4 is more exposed to the aqueous environment than in C34-cholesterol. The efficient blocking of HIV entry results from the synergic effect between the membranotropic behavior and the enhanced exposure of the PBD[1]. Maximizing antiviral activity requires finding the proper balance of membrane affinity and exposure of the peptide moiety, through variations in the lipid-binding domain, PEG spacer region, and number of peptide moieties in the construct.[1] Augusto MT et al.(2014)Improvement of the HIV fusion inhibitor C34 efficacy by membrane anchoring and enhanced exposure.J Antimicrob Chemother,69:1286-1297