Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Sanders Brian C, Pokhrel Suman, Labbe Audrey D, Mathews Irimpan I, Cooper Connor J, Davidson Russell B, Phillips Gwyndalyn, Weiss Kevin L, Zhang Qiu, O'Neill Hugh, Kaur Manat, Schmidt Jurgen G, Reichard Walter, Surendranathan Surekha, Parvathareddy Jyothi, Phillips Lexi, Rainville Christopher, Sterner David E, Kumaran Desigan, Andi Babak, Babnigg Gyorgy, Moriarty Nigel W, Adams Paul D, Joachimiak Andrzej, Hurst Brett L, Kumar Suresh, Butt Tauseef R, Jonsson Colleen B, Ferrins Lori, Wakatsuki Soichi, Galanie Stephanie, Head Martha S, Parks Jerry M
Аннотация
Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we design a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibits PLpro with kinact/KI = 9,600 M-1 s-1, achieves sub-μM EC50 values against three SARS-CoV-2 variants in mammalian cell lines, and does not inhibit a panel of human deubiquitinases (DUBs) at >30 μM concentrations of inhibitor. An X-ray co-crystal structure of the compound bound to PLpro validates our design strategy and establishes the molecular basis for covalent inhibition and selectivity against structurally similar human DUBs. These findings present an opportunity for further development of covalent PLpro inhibitors.