We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance.
- Authors
Liu, Zhanglong; Tran, Trang T.; Pham, Linh; Hu, Lingna; Bentz, Kyle; Savin, Daniel A.; Fanucci, Gail E.
- 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.
- Subjects
HIV protease inhibitors; DRUG resistance; HIV; HIGHLY active antiretroviral therapy; ELECTRON paramagnetic resonance; PARAMAGNETIC resonance; PROTEOLYTIC enzymes
- Publication
Viruses (1999-4915), 2020, Vol 12, Issue 11, p1275
- ISSN
1999-4915
- Publication type
Article
- DOI
10.3390/v12111275