The Francis Crick Institute
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Biological and structural analyses of new potent allosteric inhibitors of HIV-1 integrase.

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journal contribution
posted on 2023-07-20, 13:02 authored by Damien Bonnard, Erwann Le Rouzic, Matthew R Singer, Zhe Yu, Frédéric Le Strat, Claire Batisse, Julien Batisse, Céline Amadori, Sophie Chasset, Valerie E Pye, Stéphane Emiliani, Benoit Ledoussal, Marc Ruff, François Moreau, Peter Cherepanov, Richard Benarous
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 ( 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.


Crick (Grant ID: CC2058, Grant title: Cherepanov CC2058)