Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance
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 a...
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| Format: | Article |
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MDPI AG
2020-11-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/12/11/1275 |
| _version_ | 1797548562277466112 |
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| author | Zhanglong Liu Trang T. Tran Linh Pham Lingna Hu Kyle Bentz Daniel A. Savin Gail E. Fanucci |
| author_facet | Zhanglong Liu Trang T. Tran Linh Pham Lingna Hu Kyle Bentz Daniel A. Savin Gail E. Fanucci |
| author_sort | Zhanglong Liu |
| collection | DOAJ |
| description | 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 K<sub>i</sub> 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. |
| first_indexed | 2024-03-10T15:01:17Z |
| format | Article |
| id | doaj.art-a18e636970294c89a175945aa19760fd |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T15:01:17Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-a18e636970294c89a175945aa19760fd2023-11-20T20:11:14ZengMDPI AGViruses1999-49152020-11-011211127510.3390/v12111275Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug ResistanceZhanglong Liu0Trang T. Tran1Linh Pham2Lingna Hu3Kyle Bentz4Daniel A. Savin5Gail E. Fanucci6Department of Chemistry, University of Florida, Gainesville, FL 32611, USADepartment of Chemistry, University of Florida, Gainesville, FL 32611, USADepartment of Chemistry, University of Florida, Gainesville, FL 32611, USADepartment of Chemistry, University of Florida, Gainesville, FL 32611, USADepartment of Chemistry, University of Florida, Gainesville, FL 32611, USADepartment of Chemistry, University of Florida, Gainesville, FL 32611, USADepartment of Chemistry, University of Florida, Gainesville, FL 32611, USAMultidrug 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 K<sub>i</sub> 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.https://www.mdpi.com/1999-4915/12/11/1275HIV-1 proteasedarunavirgenetic and phenotypic diversityDEER spectroscopydrug resistance |
| spellingShingle | Zhanglong Liu Trang T. Tran Linh Pham Lingna Hu Kyle Bentz Daniel A. Savin Gail E. Fanucci Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance Viruses HIV-1 protease darunavir genetic and phenotypic diversity DEER spectroscopy drug resistance |
| title | Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance |
| title_full | Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance |
| title_fullStr | Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance |
| title_full_unstemmed | Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance |
| title_short | Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance |
| title_sort | darunavir resistant hiv 1 protease constructs uphold a conformational selection hypothesis for drug resistance |
| topic | HIV-1 protease darunavir genetic and phenotypic diversity DEER spectroscopy drug resistance |
| url | https://www.mdpi.com/1999-4915/12/11/1275 |
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