作者: Ledoussal, Benoit ; Emiliani, Stephane ; Bonnard, Damien ; Le Strat, Frederic ; Amadori, Celine ; Yu, Zhe ; Benarous, Richard ; Moreau, Francois ; Batisse, Claire ; Pye, Valerie E. ; Cherepanov, Peter ; Singer, Matthew R. ; Chasset, Sophie ; Ruff, Marc ; Le Rouzic, Erwann ; Batisse, Julien
HIV-1 integrase-LEDGF allosteric inhibitors (INLAIs) share the binding site on the viral protein with the host factor LEDGF/p75.These small mols. act as mol. 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 mols. 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 clin. 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 virol. profile of BDM-2 and the recently completed single ascending dose phase I trial warrant further clin. investigation for use in combination with other antiretroviral drugs.Moreover, our results suggest routes for further improvement of this emerging drug class.