Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I

Pawar, Shrikant; Wang, Yuan-Fang; Wong-Sam, Andres; Agniswamy, Johnson; Ghosh, Arun K.; Harrison, Robert W.; Weber, Irene T.

doi:10.1016/j.bbrc.2019.05.064

Title: Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I

Journal Article · Sun May 12 00:00:00 EDT 2019 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2019.05.064· OSTI ID:1531006

Pawar, Shrikant ^[1]; Wang, Yuan-Fang ^[1]; Wong-Sam, Andres ^[1]; Agniswamy, Johnson ^[1]; Ghosh, Arun K. ^[1]; Harrison, Robert W. ^[2];

^[1]

Georgia State Univ., Atlanta, GA (United States)
Purdue Univ., West Lafayette, IN (United States)

HIV-1 protease inhibitors are effective in HIV/AIDS therapy, although drug resistance is a severe problem. This study examines the effects of four investigational inhibitors against HIV-1 protease with drug resistant mutations of V32I, I47V and V82I (PR_Tri) that model the inhibitor-binding site of HIV-2 protease. These inhibitors contain diverse chemical modifications on the darunavir scaffold and form new interactions with wild type protease, however, the measured inhibition constants for PR_Tri mutant range from 17 to 40 nM or significantly worse than picomolar values reported for wild type enzyme. The X-ray crystal structure of PR_Tri mutant in complex with inhibitor 1 at 1.5 Å resolution shows minor changes in interactions with inhibitor compared with the corresponding wild type PR complex. Instead, the basic amine at P2 of inhibitor together with mutation V82I induces two alternate conformations for the side chain of Arg8 with new interactions with inhibitor and Leu10. Hence, inhibition is influenced by small coordinated changes in hydrophobic interactions.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Contributing Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Grant/Contract Number:: W-31–109-Eng-38; GM53386; GM062920; W-31-109-Eng-38

OSTI ID:: 1531006

Alternate ID(s):: OSTI ID: 1702259

Journal Information:: Biochemical and Biophysical Research Communications, Vol. 514, Issue 3; ISSN 0006-291X

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 11 works

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Highly drug‐resistant HIV‐1 protease reveals decreased intra‐subunit interactions due to clusters of mutations Kneller, Daniel W.; Agniswamy, Johnson; Harrison, Robert W. The FEBS Journal, Vol. 287, Issue 15 https://doi.org/10.1111/febs.15207	journal	January 2020

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Title: Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I

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