HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics

Wong-Sam, Andres; Wang, Yuan-Fang; Kneller, Daniel W.; Kovalevsky, Andrey Y.; Ghosh, Arun K.; Harrison, Robert W.; Weber, Irene T.

doi:10.1016/j.jmgm.2022.108315

HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics

Journal Article · Thu Sep 01 00:00:00 EDT 2022 · Journal of Molecular Graphics and Modelling

DOI:https://doi.org/10.1016/j.jmgm.2022.108315· OSTI ID:1887649

Wong-Sam, Andres ^[1]; Wang, Yuan-Fang ^[1]; Kneller, Daniel W. ^[2]; Kovalevsky, Andrey Y. ^[2]; Ghosh, Arun K. ^[3]; Harrison, Robert W. ^[1]; ^[1]

Georgia State Univ., Atlanta, GA (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Purdue Univ., West Lafayette, IN (United States)

Antiretroviral drug resistance is a therapeutic obstacle for people with HIV. HIV protease inhibitors darunavir and lopinavir are recommended for resistant infections. In this study, we characterized a protease mutant (PR10x) derived from a highly resistant clinical isolate including 10 mutations associated with resistance to lopinavir and darunavir. Compared to the wild-type protease, PR10x exhibits ~3-fold decrease in catalytic efficiency and K_i values of 2–3 orders of magnitude worse for darunavir, lopinavir, and potent investigational inhibitor GRL-519. Crystal structures of the mutant were solved in a ligand-free form and in complex with GRL-519. The structures show altered interactions in the active site, flap-core interface, hydrophobic core, hinge region, and 80s loop compared to the corresponding wild-type protease structures. The ligand-free crystal structure exhibits a highly curled flap conformation which may amplify drug resistance. Molecular dynamics simulations performed for 1 μs on ligand-free dimers showed extremely large fluctuations in the flaps for PR10x compared to equivalent simulations on PR with a single L76V mutation or wild-type protease. This analysis offers insight about the synergistic effects of mutations in highly resistant variants.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: Georgia State University; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC05-00OR22725; W-31109-ENG-38

OSTI ID:: 1887649

Alternate ID(s):: OSTI ID: 1887609
OSTI ID: 1901175

Journal Information:: Journal of Molecular Graphics and Modelling, Journal Name: Journal of Molecular Graphics and Modelling Journal Issue: 12 Vol. 117; ISSN 1093-3263

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
Darunavir
Drug resistance
GRL-519
HIV Protease
HIV/AIDS
Lopinavir
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X-ray crystallography

HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics

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