HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors.
Pratibha C KoneruAshwanth C FrancisNanjie DengStephanie V RebensburgAshley C HoyteJared LindenbergerDaniel Adu-AmpratwumRoss C LarueMichael F WempeAlan N EngelmanDmitry LyumkisJames R FuchsRonald M LevyGregory B MelikyanMamuka KvaratskheliaPublished in: eLife (2019)
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a promising new class of antiretroviral agents that disrupt proper viral maturation by inducing hyper-multimerization of IN. Here we show that lead pyridine-based ALLINI KF116 exhibits striking selectivity for IN tetramers versus lower order protein oligomers. IN structural features that are essential for its functional tetramerization and HIV-1 replication are also critically important for KF116 mediated higher-order IN multimerization. Live cell imaging of single viral particles revealed that KF116 treatment during virion production compromises the tight association of IN with capsid cores during subsequent infection of target cells. We have synthesized the highly active (-)-KF116 enantiomer, which displayed EC50 of ~7 nM against wild type HIV-1 and ~10 fold higher, sub-nM activity against a clinically relevant dolutegravir resistant mutant virus suggesting potential clinical benefits for complementing dolutegravir therapy with pyridine-based ALLINIs.
Keyphrases
- antiretroviral therapy
- hiv infected
- hiv positive
- human immunodeficiency virus
- hiv aids
- hiv infected patients
- hiv testing
- hepatitis c virus
- men who have sex with men
- wild type
- south africa
- sars cov
- high resolution
- induced apoptosis
- cell proliferation
- single cell
- stem cells
- risk assessment
- cell cycle arrest
- mesenchymal stem cells
- bone marrow