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

Authors
  • Liu, Zhanglong1, 2
  • Tran, Trang T.1
  • Pham, Linh1, 3
  • Hu, Lingna1
  • Bentz, Kyle1, 4
  • Savin, Daniel A.1
  • Fanucci, Gail E.1
  • 1 (D.A.S.)
  • 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
Type
Published Article
Journal
Viruses
Publisher
MDPI AG
Publication Date
Nov 08, 2020
Volume
12
Issue
11
Identifiers
DOI: 10.3390/v12111275
PMID: 33171603
PMCID: PMC7695139
Source
PubMed Central
Keywords
Disciplines
  • Article
License
Green

Abstract

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.

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