Abstract

Three integrase strand transfer inhibitors are in intensive clinical use, raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). The onset of integrase resistance mutations limits their therapeutic efficiency. As put forth earlier, the drug affinity for the intasome could be improved by targeting preferentially the retroviral nucleobases, which are little, if at all, mutation-prone. We report experimental results of anisotropy fluorescence titrations of viral DNA by these three drugs. These show the DTG > EVG > RAL ranking of their inhibitory activities of the intasome to correspond to that of their free energies of binding, ∆Gs, to retroviral DNA, and that such a ranking is only governed by the binding enthalpies, ∆H, the entropy undergoing marginal variations. We sought whether this ranking might be reproduced through quantum chemistry (QC) Density Functional Theory calculations of intermolecular interaction energies between simplified models consisting of sole halobenzene ring and the highly conserved retroviral nucleobases G4 and C16. These calculations showed that binding of EVG has a small preference over DTG, while RAL ranked third. This indicates that additional interactions of the diketoacid parts of the drugs with DNA could be necessary to further enable preferential binding of DTG. The corresponding ∆Etotvalues computed with a polarizable molecular mechanics/dynamics procedure, Sum of Interactions Between Fragments Ab initio computed (SIBFA), showed good correlations with this ∆E(QC) ranking. These validations are an important step toward the use of polarizable molecular dynamics simulations on DTG or EVG derivatives in their complexes with the complete intasome, an application now motivated and enabled by the advent of currently developed and improved massively parallel software.

Highlights

  • HIV-1 Integrase is a key element in viral replication

  • DNA strand transfer occurs in a second step, after such a complex is chaperoned into the nucleus and results in integration of viral DNA (vDNA) as a provirus into the host genome

  • As a first step toward this evaluation, we focus here on the sole halobenzene-G4/C16 interactions expressed in terms of actual enthalpies of binding and evaluate: (a) how well the ranking of ΔE(QC) intermolecular interaction energies in the ternary complexes compares to the experimental binding enthalpy ranking; (b) how well the magnitudes of ΔEtot(SIBFA) compare to those of ΔE(QC) in the three complexes and if they have the same ranking

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Summary

Introduction

HIV-1 Integrase is a key element in viral replication. In addition to its essential role in viral DNA (vDNA) integration into host genomic DNA, it is involved, directly or indirectly, in reverse transcription (Li et al, 2011), nuclear import (Engelman et al, 1995; Ikeda et al, 2004) and HIV-1 particle maturation (Balakrishnan et al, 2013; Fontana et al, 2015). In a first step, denoted as 3′-processing, a 3′GT dinucleotide is removed from each end of the long terminal repeats (LTRs) of vDNA This occurs in the cytoplasm within a multi-component pre-integration complex which gathers the vDNA and several viral and cellular proteins. DNA strand transfer occurs in a second step, after such a complex is chaperoned into the nucleus and results in integration of vDNA as a provirus into the host genome This requires cutting of two phosphodiester bonds five base pairs apart on opposite strands of the host DNA and is done by free 3′-OH groups that were liberated following LTR processing (Bushman & Craigie, 1991; Pommier, Johnson & Marchand, 2005; Lesbats, Engelman & Cherepanov, 2016).

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