Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2

Brian C. Sanders (), Suman Pokhrel, Audrey D. Labbe, Irimpan I. Mathews, Connor J. Cooper, Russell B. Davidson, Gwyndalyn Phillips, Kevin L. Weiss, Qiu Zhang, Hugh O’Neill, Manat Kaur, Jurgen G. Schmidt, Walter Reichard, Surekha Surendranathan, Jyothi Parvathareddy, Lexi Phillips, Christopher Rainville, David E. Sterner, Desigan Kumaran, Babak Andi, Gyorgy Babnigg, Nigel W. Moriarty, Paul D. Adams, Andrzej Joachimiak, Brett L. Hurst, Suresh Kumar, Tauseef R. Butt, Colleen B. Jonsson, Lori Ferrins, Soichi Wakatsuki (), Stephanie Galanie, Martha S. Head and Jerry M. Parks ()
Additional contact information
Brian C. Sanders: Oak Ridge National Laboratory
Suman Pokhrel: Stanford University School of Medicine
Audrey D. Labbe: Oak Ridge National Laboratory
Irimpan I. Mathews: Stanford Synchrotron Radiation Lightsource
Connor J. Cooper: Oak Ridge National Laboratory
Russell B. Davidson: Oak Ridge National Laboratory
Gwyndalyn Phillips: Oak Ridge National Laboratory
Kevin L. Weiss: Oak Ridge National Laboratory
Qiu Zhang: Oak Ridge National Laboratory
Hugh O’Neill: Oak Ridge National Laboratory
Manat Kaur: Stanford University School of Medicine
Jurgen G. Schmidt: Los Alamos National Laboratory
Walter Reichard: University of Tennessee Health Science Center
Surekha Surendranathan: University of Tennessee Health Science Center
Jyothi Parvathareddy: University of Tennessee Health Science Center
Lexi Phillips: Utah State University
Christopher Rainville: Progenra Inc.
David E. Sterner: Progenra Inc.
Desigan Kumaran: Brookhaven National Laboratory
Babak Andi: Brookhaven National Laboratory
Gyorgy Babnigg: University of Chicago
Nigel W. Moriarty: Lawrence Berkeley National Laboratory
Paul D. Adams: Lawrence Berkeley National Laboratory
Andrzej Joachimiak: University of Chicago
Brett L. Hurst: Utah State University
Suresh Kumar: Progenra Inc.
Tauseef R. Butt: Progenra Inc.
Colleen B. Jonsson: University of Tennessee Health Science Center
Lori Ferrins: Northeastern University
Soichi Wakatsuki: Stanford University School of Medicine
Stephanie Galanie: Oak Ridge National Laboratory
Martha S. Head: Oak Ridge National Laboratory
Jerry M. Parks: Oak Ridge National Laboratory

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37254-w

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