Structure of a HIV-1 IN-Allosteric inhibitor complex at 2.93 Å resolution: Routes to inhibitor optimization.
Grant EilersKushol GuptaAudrey AllenSaira MontermosoHemma MuraliRobert SharpYoung HwangFrederic D BushmanGregory Van DuynePublished in: PLoS pathogens (2023)
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.
Keyphrases
- sars cov
- antiretroviral therapy
- hiv positive
- hiv infected
- human immunodeficiency virus
- hiv testing
- hepatitis c virus
- small molecule
- hiv aids
- single molecule
- men who have sex with men
- high resolution
- oxidative stress
- genome wide
- magnetic resonance imaging
- cell free
- reduced graphene oxide
- gene expression
- computed tomography
- south africa
- mass spectrometry
- magnetic resonance
- dual energy
- contrast enhanced
- crystal structure