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

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 angstrom 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 pi-mediated interactions that suggest specific avenues for future ALLINI development and optimization. Author summaryThe global burden of the HIV/AIDS pandemic and continued emergence of drug resistance drives the need for novel antivirals. The allosteric integrase inhibitors, or ALLINIs, are a potent class of antivirals in development that target the enzyme integrase in a surprising fashion: the small molecules act to stabilize an inappropriate protein-protein interaction to attain biological effect. Here, we report the first atomic resolution (2.93 angstrom) X-ray crystal structure of the minimal ternary complex between domains of the integrase and the first ALLINI preclinical lead BI-224436. Our structure provides a more precise view of the molecular interactions that underlie drug potency, and several aspects of our data suggest routes to improving ALLINI design and minimizing acquisition of resistance.

Automated summary

HIV integrase plays a crucial role in viral replication by inserting viral DNA into the host genome. Strand transfer inhibitors (STIs) and allosteric inhibitors of integrase (ALLINIs) are two major classes of antivirals that target integrase. In this study, we determined the crystal structure of the minimal ternary complex between the catalytic core domain (CCD), carboxy-terminal domain (CTD), and the ALLINI BI-224436, providing insights for improving ALLINI design and minimizing resistance.