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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Detalles Bibliográficos
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
Descripción
Sumario: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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