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Efficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase mutants
BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the FDA for the treatment of HIV-1 infections. INSTIs block the strand transfer reaction catalyzed by HIV-1 integrase (IN) and have been shown to potently inhibit infection...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956922/ https://www.ncbi.nlm.nih.gov/pubmed/29769116 http://dx.doi.org/10.1186/s12977-018-0420-7 |
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author | Smith, Steven J. Zhao, Xue Zhi Burke, Terrence R. Hughes, Stephen H. |
author_facet | Smith, Steven J. Zhao, Xue Zhi Burke, Terrence R. Hughes, Stephen H. |
author_sort | Smith, Steven J. |
collection | PubMed |
description | BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the FDA for the treatment of HIV-1 infections. INSTIs block the strand transfer reaction catalyzed by HIV-1 integrase (IN) and have been shown to potently inhibit infection by wild-type HIV-1. Of the three current FDA-approved INSTIs, Dolutegravir (DTG), has been the most effective, in part because treatment does not readily select for resistant mutants. However, recent studies showed that when INSTI-experienced patients are put on a DTG-salvage therapy, they have reduced response rates. Two new INSTIs, Cabotegravir (CAB) and Bictegravir (BIC), are currently in late-stage clinical trials. RESULTS: Both CAB and BIC had much broader antiviral profiles than RAL and EVG against the INSTI-resistant single, double, and triple HIV-1 mutants used in this study. BIC was more effective than DTG against several INSTI-resistant mutants. Overall, in terms of their ability to inhibit a broad range of INSTI-resistant IN mutants, BIC was superior to DTG, and DTG was superior to CAB. Modeling the binding of CAB, BIC, and DTG within the active site of IN suggested that the “left side” of the INSTI pharmacophore (the side away from the viral DNA) was important in determining the ability of the compound to inhibit the IN mutants we tested. CONCLUSIONS: Of the two INSTIs in late stage clinical trials, BIC appears to be better able to inhibit the replication of a broad range of IN mutants. BIC retained potency against several of the INSTI-resistant mutants that caused a decrease in susceptibility to DTG. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12977-018-0420-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5956922 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-59569222018-05-24 Efficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase mutants Smith, Steven J. Zhao, Xue Zhi Burke, Terrence R. Hughes, Stephen H. Retrovirology Research BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the FDA for the treatment of HIV-1 infections. INSTIs block the strand transfer reaction catalyzed by HIV-1 integrase (IN) and have been shown to potently inhibit infection by wild-type HIV-1. Of the three current FDA-approved INSTIs, Dolutegravir (DTG), has been the most effective, in part because treatment does not readily select for resistant mutants. However, recent studies showed that when INSTI-experienced patients are put on a DTG-salvage therapy, they have reduced response rates. Two new INSTIs, Cabotegravir (CAB) and Bictegravir (BIC), are currently in late-stage clinical trials. RESULTS: Both CAB and BIC had much broader antiviral profiles than RAL and EVG against the INSTI-resistant single, double, and triple HIV-1 mutants used in this study. BIC was more effective than DTG against several INSTI-resistant mutants. Overall, in terms of their ability to inhibit a broad range of INSTI-resistant IN mutants, BIC was superior to DTG, and DTG was superior to CAB. Modeling the binding of CAB, BIC, and DTG within the active site of IN suggested that the “left side” of the INSTI pharmacophore (the side away from the viral DNA) was important in determining the ability of the compound to inhibit the IN mutants we tested. CONCLUSIONS: Of the two INSTIs in late stage clinical trials, BIC appears to be better able to inhibit the replication of a broad range of IN mutants. BIC retained potency against several of the INSTI-resistant mutants that caused a decrease in susceptibility to DTG. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12977-018-0420-7) contains supplementary material, which is available to authorized users. BioMed Central 2018-05-16 /pmc/articles/PMC5956922/ /pubmed/29769116 http://dx.doi.org/10.1186/s12977-018-0420-7 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Smith, Steven J. Zhao, Xue Zhi Burke, Terrence R. Hughes, Stephen H. Efficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase mutants |
title | Efficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase mutants |
title_full | Efficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase mutants |
title_fullStr | Efficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase mutants |
title_full_unstemmed | Efficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase mutants |
title_short | Efficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase mutants |
title_sort | efficacies of cabotegravir and bictegravir against drug-resistant hiv-1 integrase mutants |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956922/ https://www.ncbi.nlm.nih.gov/pubmed/29769116 http://dx.doi.org/10.1186/s12977-018-0420-7 |
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