Energetics of dendrimer binding to HIV-1 gp120-CD4 complex and mechanismic aspects of its role as an entry-inhibitor

Suman Saurabh,Anil Kumar Sahoo,Prabal K Maiti

doi:10.1088/1742-6596/759/1/012020

Suman Saurabh, Anil Kumar Sahoo + Show 1 more

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https://doi.org/10.1088/1742-6596/759/1/012020

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Abstract

Experiments and computational studies have established that de-protonated dendrimers (SPL7013 and PAMAM) act as entry-inhibitors of HIV. SPL7013 based Vivagel is currently under clinical development. The dendrimer binds to gp120 in the gp120-CD4 complex, destabilizes it by breaking key contacts between gp120 and CD4 and prevents viral entry into target cells. In this work, we provide molecular details and energetics of the formation of the SPL7013-gp120-CD4 ternary complex and decipher modes of action of the dendrimer in preventing viral entry. It is also known from experiments that the dendrimer binds weakly to gp120 that is not bound to CD4. It binds even more weakly to the CD4-binding region of gp120 and thus cannot directly block gp120-CD4 complexation. In this work, we examine the feasibility of dendrimer binding to the gp120-binding region of CD4 and directly blocking gp120-CD4 complex formation. We find that the process of the dendrimer binding to CD4 can compete with gp120-CD4 binding due to comparable free energy change for the two processes, thus creating a possibility for the dendrimer to directly block gp120-CD4 complexation by binding to the gp120-binding region of CD4.

Highlights

The entry of HIV into target CD4+ T cells in humans is initiated by the binding of the viral surface protein gp120 to the target cell receptor protein CD4 [1]
This binding induces structural changes in gp120, which help it bind to the target cell trans-membrane protein CCR5 or CXCR4 leading to further conformational changes resulting in membrane fusion
We find that the terminal groups of the dendrimer are placed very close to the positively charged residues of gp120 (∼5 ̊A), whereas the average distance from the hydrophobic residues is a bit larger (∼7.5 ̊A) and the corresponding peaks are smaller than those corresponding to the positively charged residues

Summary

Introduction

The entry of HIV into target CD4+ T cells in humans is initiated by the binding of the viral surface protein gp120 to the target cell receptor protein CD4 [1]. This binding induces structural changes in gp120, which help it bind to the target cell trans-membrane protein CCR5 or CXCR4 leading to further conformational changes resulting in membrane fusion. The disruption of binding between the proteins that facilitate viral entry is one of the many drug-discovery strategies aimed at developing an HIV inhibitor. The multivalent nature of the dendrimer allows it to bind in multiple possible conformations with various bio-molecules

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