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

Antimicrob Agents Chemother. 2023 Jul 18;67(7):e0046223. doi: 10.1128/aac.00462-23. Epub 2023 Jun 13.


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.

Keywords: ALLINI; HIV-1; LEDGF; allosteric inhibitor; antiretrovirals; cocrystallization.; drug discovery; integrase; integrase inhibitor; molecular glue; protein-protein interaction inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Antiviral Agents / pharmacology
  • HIV Infections* / drug therapy
  • HIV Integrase Inhibitors* / pharmacology
  • HIV Integrase Inhibitors* / therapeutic use
  • HIV Integrase* / metabolism
  • Humans
  • Virus Replication


  • p31 integrase protein, Human immunodeficiency virus 1
  • HIV Integrase Inhibitors
  • Antiviral Agents
  • HIV Integrase

Associated data