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

Grant Eilers, Kushol Gupta, Audrey Allen, Saira Montermoso, Hemma Murali, Robert Sharp, Young Hwang, Frederic D Bushman, Gregory Van Duyne

PLoS pathogens 2023 Mar

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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. Copyright: © 2023 Eilers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Grant Eilers, Kushol Gupta, Audrey Allen, Saira Montermoso, Hemma Murali, Robert Sharp, Young Hwang, Frederic D Bushman, Gregory Van Duyne. Structure of a HIV-1 IN-Allosteric inhibitor complex at 2.93 Å resolution: Routes to inhibitor optimization. PLoS pathogens. 2023 Mar;19(3):e1011097