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Article

Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance

1
Department of Chemistry, University of Florida, Gainesville, FL 32611, USA
2
LinkedIn, Mountain View, Sunnyvale, CA 94043, USA
3
Department of Science and Mathematics, Texas A&M University—Central Texas, Killeen, TX 76549, USA
4
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA
*
Author to whom correspondence should be addressed.
Viruses 2020, 12(11), 1275; https://doi.org/10.3390/v12111275
Received: 24 September 2020 / Revised: 23 October 2020 / Accepted: 30 October 2020 / Published: 8 November 2020
(This article belongs to the Special Issue Diversity and Evolution of HIV and HCV)
Multidrug resistance continues to be a barrier to the effectiveness of highly active antiretroviral therapy in the treatment of human immunodeficiency virus 1 (HIV-1) infection. Darunavir (DRV) is a highly potent protease inhibitor (PI) that is oftentimes effective when drug resistance has emerged against first-generation inhibitors. Resistance to darunavir does evolve and requires 10–20 amino acid substitutions. The conformational landscapes of six highly characterized HIV-1 protease (PR) constructs that harbor up to 19 DRV-associated mutations were characterized by distance measurements with pulsed electron double resonance (PELDOR) paramagnetic resonance spectroscopy, namely double electron–electron resonance (DEER). The results show that the accumulated substitutions alter the conformational landscape compared to PI-naïve protease where the semi-open conformation is destabilized as the dominant population with open-like states becoming prevalent in many cases. A linear correlation is found between values of the DRV inhibition parameter Ki and the open-like to closed-state population ratio determined from DEER. The nearly 50% decrease in occupancy of the semi-open conformation is associated with reduced enzymatic activity, characterized previously in the literature. View Full-Text
Keywords: HIV-1 protease; darunavir; genetic and phenotypic diversity; DEER spectroscopy; drug resistance HIV-1 protease; darunavir; genetic and phenotypic diversity; DEER spectroscopy; drug resistance
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MDPI and ACS Style

Liu, Z.; Tran, T.T.; Pham, L.; Hu, L.; Bentz, K.; Savin, D.A.; Fanucci, G.E. Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance. Viruses 2020, 12, 1275. https://doi.org/10.3390/v12111275

AMA Style

Liu Z, Tran TT, Pham L, Hu L, Bentz K, Savin DA, Fanucci GE. Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance. Viruses. 2020; 12(11):1275. https://doi.org/10.3390/v12111275

Chicago/Turabian Style

Liu, Zhanglong, Trang T. Tran, Linh Pham, Lingna Hu, Kyle Bentz, Daniel A. Savin, and Gail E. Fanucci 2020. "Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance" Viruses 12, no. 11: 1275. https://doi.org/10.3390/v12111275

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