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

摘要

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 > dolute-gravir (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 G140S1+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.