Dataset Information

Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy.

ABSTRACT: Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more closely with the drugs than with the natural substrate peptides. The V82A mutation compromises these interactions with the drugs while not greatly affecting the substrate interactions, which is consistent with previously published kinetic data. Coupled with our earlier observations, these findings suggest that future inhibitor design may reduce the probability of the appearance of drug-resistant mutations by targeting residues that are essential for substrate recognition.

SUBMITTER: Prabu-Jeyabalan M

PROVIDER: S-EPMC140781 | biostudies-literature | 2003 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy.

Prabu-Jeyabalan Moses M Nalivaika Ellen A EA King Nancy M NM Schiffer Celia A CA

Journal of virology 20030101 2

Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and ...[more]

PMID: 12502847

Similar Datasets

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

Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy.

Publications

Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets