Computer-aided design of novel HIV-1 entry inhibitors blocking the virus envelope gp120 V3 loop

A M Andrianov,V A Nikolayevich,V F Eremin,Yu V Kornoushenko,I V Anishchenko,M A Kisel,I I Kucherov,A V Tuzikov

doi:10.7124/bc.000139

Abstract

Aim. The object of this study was to implement computer-aided design of the water-soluble analog of glycolipid β-galactosylceramide (β-GalCer), which presents a potential HIV-1 entry inhibitor, by the analysis of intermolecular interactions of β-GalCer with the central region of the virus envelope gp120 V3 loop followed by synthesis of this glycolipid derivative and testing for antiviral activity. Methods. To reach the object of view, computer modeling procedures, such as quantum chemical calculations, molecular docking, molecular dynamics and free energy simulations, were involved in the studies in conjunction with chemical synthesis and anti-HIV-1 assay methods. Results. As a result, the high probability of exhibiting of antiviral activity was predicted for the designed β-GalCer analog. The data of molecular modeling were confirmed by those of primary medical trials of the synthesized compound. Conclusions. In the light of the findings obtained, the designed analog of β-GalCer may be considered as the basic structure for simulation of its more potent structural forms and for posterior selection of drug candidates most promising for synthesis and anti-HIV-1 assays.

Highlights

The HIV-1 V3 loop plays a central role in the biology of the HIV-1 envelope glycoprotein gp120 as a principal target for neutralizing antibodies, and as a major determinant in the switch from the non-syncytium-inducing to the syncytium-inducing form of HIV-1 that is associated with accelerated disease progression
Β-galactosylceramide (β-GalCer) forms on the surface of some susceptible host cells the primary receptor for HIV-1 alternative to CD4, which is used by the virus to enter macrophages and T-lymphocytes (e. g., [7])
The high probability of displaying the antiviral activity was predicted for the simulated molecule by estimating the free energy of formation of the structures for this β-GalCer derivative complexed with the V3 loop peptides

Summary

Introduction

The HIV-1 V3 loop plays a central role in the biology of the HIV-1 envelope glycoprotein gp120 as a principal target for neutralizing antibodies, and as a major determinant in the switch from the non-syncytium-inducing to the syncytium-inducing form of HIV-1 that is associated with accelerated disease progression. The V3 loop is a promising target for anti-HIV-1 drug design, its high sequence variability is a major complicating factor [3]. COMPUTER-AIDED DESIGN OF NOVEL HIV-1 ENTRY INHIBITORS BLOCKING THE VIRUS ENVELOPE gp120 V3 LOOP son, may be implicated in the V3-based anti-AIDS drug studies (reviewed in [2]). Some water soluble analogs of this glycosphingolipid have been shown to inhibit cell tropism by specific binding to V3 The findings of a study [8] have shown that synthetic analogs of β-GalCer can inhibit the HIV-1 entry both into CD4– and CD4+ cells by masking the HIV-1 V3 loop. Specific interactions of the HIV-1 V3 loop with β-GalCer were specified in a study of Hammache and coauthors [11] by measuring surface tension variations occurring on gp120 binding to monolayers of glycolipids. In a recent study [12], glycoside analogs of β-GalCer have been shown to block the envelope gp120 V3 loop

Objectives

Methods

Results

Conclusion