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Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease.

ABSTRACT: The use of antiretroviral drugs is accompanied by the emergence of HIV-2 resistances. Thus, it is important to elucidate the mechanisms of resistance to antiretroviral drugs. Here, we propose a structural analysis of 31 drug-resistant mutants of HIV-2 protease (PR2) that is an important target against HIV-2 infection. First, we modeled the structures of each mutant. We then located structural shifts putatively induced by mutations. Finally, we compared wild-type and mutant inhibitor-binding pockets and interfaces to explore the impacts of these induced structural deformations on these two regions. Our results showed that one mutation could induce large structural rearrangements in side-chain and backbone atoms of mutated residue, in its vicinity or further. Structural deformations observed in side-chain atoms are frequent and of greater magnitude, that confirms that to fight drug resistance, interactions with backbone atoms should be favored. We showed that these observed structural deformations modify the conformation, volume, and hydrophobicity of the binding pocket and the composition and size of the PR2 interface. These results suggest that resistance mutations could alter ligand binding by modifying pocket properties and PR2 stability by impacting its interface. Our results reinforce the understanding of the effects of mutations that occurred in PR2 and the different mechanisms of PR2 resistance.

SUBMITTER: Laville P

PROVIDER: S-EPMC7865771 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease.

Laville Pierre P Petitjean Michel M Regad Leslie L

Molecules (Basel, Switzerland) 20210125 3

The use of antiretroviral drugs is accompanied by the emergence of HIV-2 resistances. Thus, it is important to elucidate the mechanisms of resistance to antiretroviral drugs. Here, we propose a structural analysis of 31 drug-resistant mutants of HIV-2 protease (PR2) that is an important target against HIV-2 infection. First, we modeled the structures of each mutant. We then located structural shifts putatively induced by mutations. Finally, we compared wild-type and mutant inhibitor-binding pock ...[more]

PMID: 33503916

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Project description:BackgroundStrategies to control HIV for improving the quality of patient lives have been aided by the Highly Active Anti-Retroviral Therapy (HAART), which consists of a cocktail of inhibitors targeting key viral enzymes. Numerous new drugs have been developed over the past few decades but viral resistances to these drugs in the targeted viral enzymes are increasingly reported. Nonetheless the acquired mutations often reduce viral fitness and infectivity. Viral compensatory secondary-line mutations mitigate this loss of fitness, equipping the virus with a broad spectrum of resistance against these drugs. While structural understanding of the viral protease and its drug resistance mutations have been well established, the interconnectivity and development of structural cross-resistance remain unclear. This paper reports the structural analyses of recent clinical mutations on the drug cross-resistance effects from various protease and protease inhibitors (PIs) complexes.MethodsUsing the 2015 updated clinical HIV protease mutations, we constructed a structure-based correlation network and a minimum-spanning tree (MST) based on the following features: (i) topology of the PI-binding pocket, (ii) allosteric effects of the mutations, and (iii) protease structural stability.Results and conclusionAnalyis of the network and the MST of dominant mutations conferring resistance to the seven PIs (Atazanavir-ATV, Darunavir-DRV, Indinavir-IDV, Lopinavir-LPV, Nelfinavir-NFV, Saquinavir-SQV, and Tipranavir-TPV) showed that cross-resistance can develop easily across NFV, SQV, LPV, IDV, and DRV, but not for ATV or TPV. Through estimation of the changes in vibrational entropies caused by each reported mutation, some secondary mutations were found to destabilize protease structure. Our findings provide an insight into the mechanism of PI cross-resistance and may also be useful in guiding the selection of PI in clinical treatment to delay the onset of cross drug resistance.

Dataset Information

Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease.

Publications

Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease.

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