Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes

The HIV integrase (IN) strand transfer inhibitor (INSTI) bictegravir (BIC) has a long dissociation half-life (t(1/2)) from wild-type IN-DNA complexes: BIC 163 h > dolutegravir (DTG) 96 h > raltegravir (RAL) 10 h > elvitegravir (EVG) 3.3 h. In cells, BIC had more durable antiviral activity a...

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Autores principales: White, Kirsten L., Osman, Nathan, Cuadra-Foy, Ernesto, Brenner, Bluma G., Shivakumar, Devleena, Campigotto, Federico, Tsiang, Manuel, Morganelli, Philip A., Novikov, Nikolai, Lazerwith, Scott E., Jin, Haolun, Niedziela-Majka, Anita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2021
Materias:
Antiviral Agents
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092912/
https://www.ncbi.nlm.nih.gov/pubmed/33649107
http://dx.doi.org/10.1128/AAC.02406-20
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author White, Kirsten L.
Osman, Nathan
Cuadra-Foy, Ernesto
Brenner, Bluma G.
Shivakumar, Devleena
Campigotto, Federico
Tsiang, Manuel
Morganelli, Philip A.
Novikov, Nikolai
Lazerwith, Scott E.
Jin, Haolun
Niedziela-Majka, Anita
author_facet White, Kirsten L.
Osman, Nathan
Cuadra-Foy, Ernesto
Brenner, Bluma G.
Shivakumar, Devleena
Campigotto, Federico
Tsiang, Manuel
Morganelli, Philip A.
Novikov, Nikolai
Lazerwith, Scott E.
Jin, Haolun
Niedziela-Majka, Anita
author_sort White, Kirsten L.
collection PubMed
description The HIV integrase (IN) strand transfer inhibitor (INSTI) bictegravir (BIC) has a long dissociation half-life (t(1/2)) from wild-type IN-DNA complexes: BIC 163 h > dolutegravir (DTG) 96 h > raltegravir (RAL) 10 h > elvitegravir (EVG) 3.3 h. In cells, BIC had more durable antiviral activity against wild-type HIV after drug washout than RAL or EVG. BIC also had a longer t(1/2) and maintained longer antiviral activity after drug washout than DTG with the clinically relevant resistance IN mutant G140S+Q148H. Structural analyses indicate that BIC makes more contacts with the IN-DNA complex than DTG mainly via its bicyclic ring system, which may contribute to more prolonged residence time and resilience against many resistance mutations.
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spelling pubmed-80929122021-10-19 Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes White, Kirsten L. Osman, Nathan Cuadra-Foy, Ernesto Brenner, Bluma G. Shivakumar, Devleena Campigotto, Federico Tsiang, Manuel Morganelli, Philip A. Novikov, Nikolai Lazerwith, Scott E. Jin, Haolun Niedziela-Majka, Anita Antimicrob Agents Chemother Antiviral Agents The HIV integrase (IN) strand transfer inhibitor (INSTI) bictegravir (BIC) has a long dissociation half-life (t(1/2)) from wild-type IN-DNA complexes: BIC 163 h > dolutegravir (DTG) 96 h > raltegravir (RAL) 10 h > elvitegravir (EVG) 3.3 h. In cells, BIC had more durable antiviral activity against wild-type HIV after drug washout than RAL or EVG. BIC also had a longer t(1/2) and maintained longer antiviral activity after drug washout than DTG with the clinically relevant resistance IN mutant G140S+Q148H. Structural analyses indicate that BIC makes more contacts with the IN-DNA complex than DTG mainly via its bicyclic ring system, which may contribute to more prolonged residence time and resilience against many resistance mutations. American Society for Microbiology 2021-04-19 /pmc/articles/PMC8092912/ /pubmed/33649107 http://dx.doi.org/10.1128/AAC.02406-20 Text en Copyright © 2021 White et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Antiviral Agents
White, Kirsten L.
Osman, Nathan
Cuadra-Foy, Ernesto
Brenner, Bluma G.
Shivakumar, Devleena
Campigotto, Federico
Tsiang, Manuel
Morganelli, Philip A.
Novikov, Nikolai
Lazerwith, Scott E.
Jin, Haolun
Niedziela-Majka, Anita
Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes
title Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes
title_full Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes
title_fullStr Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes
title_full_unstemmed Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes
title_short Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes
title_sort long dissociation of bictegravir from hiv-1 integrase-dna complexes
topic Antiviral Agents
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092912/
https://www.ncbi.nlm.nih.gov/pubmed/33649107
http://dx.doi.org/10.1128/AAC.02406-20
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