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

[tetano]

Nat Commun


. 2023 Mar 28;14(1):1733.
doi: 10.1038/s41467-023-37254-w.
Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2


Brian C Sanders ^{# 1} , Suman Pokhrel ^{# 2 3} , Audrey D Labbe ⁴ , Irimpan I Mathews ⁵ , Connor J Cooper ⁴ , Russell B Davidson ⁴ , Gwyndalyn Phillips ⁶ , Kevin L Weiss ⁶ , Qiu Zhang ⁶ , Hugh O'Neill ⁶ , Manat Kaur ⁷ , Jurgen G Schmidt ⁸ , Walter Reichard ⁹ , Surekha Surendranathan ¹⁰ , Jyothi Parvathareddy ¹⁰ , Lexi Phillips ¹¹ , Christopher Rainville ¹² , David E Sterner ¹² , Desigan Kumaran ¹³ , Babak Andi ¹⁴ , Gyorgy Babnigg ^{15 16} , Nigel W Moriarty ¹⁷ , Paul D Adams ^{17 18} , Andrzej Joachimiak ^{15 19 20} , Brett L Hurst ¹¹ , Suresh Kumar ¹² , Tauseef R Butt ¹² , Colleen B Jonsson ⁹ , Lori Ferrins ²¹ , Soichi Wakatsuki ^{22 23 24} , Stephanie Galanie ^{4 25} , Martha S Head ^{26 27 28} , Jerry M Parks ²⁹



Affiliations

• PMID: 36977673
• DOI: 10.1038/s41467-023-37254-w

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 k_inact/K_I = 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.