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Koneru PC , Francis AC , Deng N , Rebensburg SV , Hoyte AC , Lindenberger J , Adu-Ampratwum D , Larue RC , Wempe MF , Engelman AN , Lyumkis D , Fuchs JR , Levy RM , Melikyan GB , Kvaratskhelia M
HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors
Elife. 2019 May 23;8
PMID: 31120420    PMCID: PMC6581505   
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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.
2050-084x Koneru, Pratibha C Orcid: 0000-0003-3955-4548 Francis, Ashwanth C Deng, Nanjie Rebensburg, Stephanie V Hoyte, Ashley C Lindenberger, Jared Adu-Ampratwum, Daniel Orcid: 0000-0001-9392-2431 Larue, Ross C Wempe, Michael F Engelman, Alan N Lyumkis, Dmitry Orcid: 0000-0002-8124-7472 Fuchs, James R Levy, Ronald M Orcid: 0000-0001-8696-5177 Melikyan, Gregory B Kvaratskhelia, Mamuka Orcid: 0000-0003-3800-0033 R01 AI136680/AI/NIAID NIH HHS/United States R01 AI143649/AI/NIAID NIH HHS/United States R37 AI039394/AI/NIAID NIH HHS/United States R01AI129862/NH/NIH HHS/United States KL2 TR001068/NH/NIH HHS/United States R01AI143649/NH/NIH HHS/United States R01AI062520/NH/NIH HHS/United States R01 AI062520/AI/NIAID NIH HHS/United States U54GM103368/NH/NIH HHS/United States R01 AI129862/AI/NIAID NIH HHS/United States R37AI039394/NH/NIH HHS/United States Journal Article Research Support, N.I.H., Extramural England Elife. 2019 May 23;8. pii: 46344. doi: 10.7554/eLife.46344.