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

Autor:	Bonnard D; Biodim, Romainville, France., Le Rouzic E; Biodim, Romainville, France., Singer MR; Chromatin Structure and Mobile DNA Laboratory, Francis Crick Institute, London, United Kingdom., Yu Z; Chromatin Structure and Mobile DNA Laboratory, Francis Crick Institute, London, United Kingdom., Le Strat F; Biodim, Romainville, France., Batisse C; IGBMC, INSERM, CNRS, Université de Strasbourg, Illkirch, France., Batisse J; IGBMC, INSERM, CNRS, Université de Strasbourg, Illkirch, France., Amadori C; Biodim, Romainville, France.; Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France., Chasset S; Biodim, Romainville, France., Pye VE; Chromatin Structure and Mobile DNA Laboratory, Francis Crick Institute, London, United Kingdom., Emiliani S; Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France., Ledoussal B; Biodim, Romainville, France., Ruff M; IGBMC, INSERM, CNRS, Université de Strasbourg, Illkirch, France., Moreau F; Biodim, Romainville, France., Cherepanov P; Chromatin Structure and Mobile DNA Laboratory, Francis Crick Institute, London, United Kingdom.; Department of Infectious Disease, St. Mary's Campus, Imperial College London, London, United Kingdom., Benarous R; Biodim, Romainville, France.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2023 Jul 18; Vol. 67 (7), pp. e0046223. Date of Electronic Publication: 2023 Jun 13.
DOI:	10.1128/aac.00462-23
Abstrakt:	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.
Databáze:	MEDLINE
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