Structure of a HIV-1 IN-Allosteric inhibitor complex at 2.93 Å resolution: Routes to inhibitor optimization

PLoS Pathog. 2023 Mar 3;19(3):e1011097. doi: 10.1371/journal.ppat.1011097. eCollection 2023 Mar.


HIV integrase (IN) inserts viral DNA into the host genome and is the target of the strand transfer inhibitors (STIs), a class of small molecules currently in clinical use. Another potent class of antivirals is the allosteric inhibitors of integrase, or ALLINIs. ALLINIs promote IN aggregation by stabilizing an interaction between the catalytic core domain (CCD) and carboxy-terminal domain (CTD) that undermines viral particle formation in late replication. Ongoing challenges with inhibitor potency, toxicity, and viral resistance motivate research to understand their mechanism. Here, we report a 2.93 Å X-ray crystal structure of the minimal ternary complex between CCD, CTD, and the ALLINI BI-224436. This structure reveals an asymmetric ternary complex with a prominent network of π-mediated interactions that suggest specific avenues for future ALLINI development and optimization.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Antiviral Agents
  • Catalytic Domain
  • HIV Integrase Inhibitors* / pharmacology
  • HIV Integrase* / genetics
  • HIV-1* / metabolism


  • HIV Integrase Inhibitors
  • Antiviral Agents
  • HIV Integrase