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HIV-1 Protease: Structural Perspectives on Drug Resistance.

ABSTRACT: Antiviral inhibitors of HIV-1 protease are a notable success of structure-based drug design and have dramatically improved AIDS therapy. Analysis of the structures and activities of drug resistant protease variants has revealed novel molecular mechanisms of drug resistance and guided the design of tight-binding inhibitors for resistant variants. The plethora of structures reveals distinct molecular mechanisms associated with resistance: mutations that alter the protease interactions with inhibitors or substrates; mutations that alter dimer stability; and distal mutations that transmit changes to the active site. These insights will inform the continuing design of novel antiviral inhibitors targeting resistant strains of HIV.

SUBMITTER: Weber IT

PROVIDER: S-EPMC3185505 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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HIV-1 Protease: Structural Perspectives on Drug Resistance.

Weber Irene T IT Agniswamy Johnson J

Viruses 20091203 3

Antiviral inhibitors of HIV-1 protease are a notable success of structure-based drug design and have dramatically improved AIDS therapy. Analysis of the structures and activities of drug resistant protease variants has revealed novel molecular mechanisms of drug resistance and guided the design of tight-binding inhibitors for resistant variants. The plethora of structures reveals distinct molecular mechanisms associated with resistance: mutations that alter the protease interactions with inhibit ...[more]

PMID: 21994585

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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

HIV-1 Protease: Structural Perspectives on Drug Resistance.

Publications

HIV-1 Protease: Structural Perspectives on Drug Resistance.

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