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Journal Articles Antimicrobial Agents and Chemotherapy Year : 2023

Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase

Abstract

HIV-1 integrase-LEDGF allosteric inhibitors (INLAIs) share the binding site on the viral protein with the host factor LEDGF/p75. These small molecules act as molecular glues promoting hyper-multimerization of HIV-1 IN protein to severely perturb maturation of viral particles. Herein, we describe a new series of INLAIs based on a benzene scaffold that display antiviral activity in the single digit nanomolar range. Akin to other compounds of this class, the INLAIs predominantly inhibit the late stages of HIV-1 replication. A series of high-resolution crystal structures revealed how these small molecules engage the catalytic core and the C-terminal domains of HIV-1 IN. No antagonism was observed between our lead INLAI compound BDM-2 and a panel of 16 clinical antiretrovirals. Moreover, we show that compounds retained high antiviral activity against HIV-1 variants resistant to IN strand transfer inhibitors and other classes of antiretroviral drugs. The virologic profile of BDM-2 and the recently completed single ascending dose phase I trial (ClinicalTrials.gov identifier: NCT03634085) warrant further clinical investigation for use in combination with other antiretroviral drugs. Moreover, our results suggest routes for further improvement of this emerging drug class.
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Dates and versions

hal-04219166 , version 1 (26-09-2023)

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Damien Bonnard, Erwann Le Rouzic, Matthew Singer, Zhe Yu, Frédéric Le Strat, et al.. Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase. Antimicrobial Agents and Chemotherapy, 2023, 67 (7), ⟨10.1128/aac.00462-23⟩. ⟨hal-04219166⟩
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