8BV2

Biological and structural analysis of new potent Integrase-LEDGF allosteric HIV-1 inhibitors

Summary for 8BV2

• Entry DOI: 10.2210/pdb8bv2/pdb
• Descriptor: Integrase, (2S)-2-[3-cyclopropyl-2-(3,4-dihydro-2H-chromen-6-yl)-6-methyl-phenyl]-2-[(2-methylpropan-2-yl)oxy]ethanoic acid, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: inhibitors, integrase, hiv-1, viral protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 20654.52

Authors

Ruff, M.,Benarous, R. (deposition date: 2022-12-01, release date: 2023-06-07, Last modification date: 2024-10-23)

Primary citation

Bonnard, D.,Le Rouzic, E.,Singer, M.R.,Yu, Z.,Le Strat, F.,Batisse, C.,Batisse, J.,Amadori, C.,Chasset, S.,Pye, V.E.,Emiliani, S.,Ledoussal, B.,Ruff, M.,Moreau, F.,Cherepanov, P.,Benarous, R.
Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase.
Antimicrob.Agents Chemother., 67:e0046223-e0046223, 2023

PubMed 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.

PubMed: 37310224
DOI: 10.1128/aac.00462-23

Experimental method

X-RAY DIFFRACTION (2 Å)