Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase - Archive ouverte HAL
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.
Fichier principal
Vignette du fichier
islandora_167400.pdf (1.64 Mo) Télécharger le fichier
Origin Files produced by the author(s)

Dates and versions

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

Identifiers

Cite

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⟩
41 View
31 Download

Altmetric

Share

More