skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

Abstract

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.

Authors:
 [1];  [1];  [1];  [1];  [1];  [2]; ORCiD logo [1]
  1. Georgia State Univ., Atlanta, GA (United States)
  2. Purdue Univ., West Lafayette, IN (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Contributing Org.:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
OSTI Identifier:
1531006
Alternate Identifier(s):
OSTI ID: 1702259
Grant/Contract Number:  
W-31–109-Eng-38; GM53386; GM062920; W-31-109-Eng-38
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 514; Journal Issue: 3; Journal ID: ISSN 0006-291X
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; HIV-1 protease; Antiviral inhibitors; Drug resistance; X-ray crystallography

Citation Formats

Pawar, Shrikant, Wang, Yuan-Fang, Wong-Sam, Andres, Agniswamy, Johnson, Ghosh, Arun K., Harrison, Robert W., and Weber, Irene T. Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I. United States: N. p., 2019. Web. doi:10.1016/j.bbrc.2019.05.064.
Pawar, Shrikant, Wang, Yuan-Fang, Wong-Sam, Andres, Agniswamy, Johnson, Ghosh, Arun K., Harrison, Robert W., & Weber, Irene T. Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I. United States. https://doi.org/10.1016/j.bbrc.2019.05.064
Pawar, Shrikant, Wang, Yuan-Fang, Wong-Sam, Andres, Agniswamy, Johnson, Ghosh, Arun K., Harrison, Robert W., and Weber, Irene T. Sun . "Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I". United States. https://doi.org/10.1016/j.bbrc.2019.05.064. https://www.osti.gov/servlets/purl/1531006.
@article{osti_1531006,
title = {Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I},
author = {Pawar, Shrikant and Wang, Yuan-Fang and Wong-Sam, Andres and Agniswamy, Johnson and Ghosh, Arun K. and Harrison, Robert W. and Weber, Irene T.},
abstractNote = {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 (PRTri) 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 PRTri mutant range from 17 to 40 nM or significantly worse than picomolar values reported for wild type enzyme. The X-ray crystal structure of PRTri 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.},
doi = {10.1016/j.bbrc.2019.05.064},
url = {https://www.osti.gov/biblio/1531006}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 514,
place = {United States},
year = {2019},
month = {5}
}

Journal Article:

Citation Metrics:
Cited by: 6 works
Citation information provided by
Web of Science

Save / Share:

Works referencing / citing this record:

Highly drug‐resistant HIV‐1 protease reveals decreased intra‐subunit interactions due to clusters of mutations
journal, January 2020