Targeting papain-like protease for broad-spectrum coronavirus inhibition.
Nsp3
antiviral
coronavirus
inhibitor
protease
Journal
Protein & cell
ISSN: 1674-8018
Titre abrégé: Protein Cell
Pays: Germany
ID NLM: 101532368
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
01
09
2021
accepted:
17
02
2022
pubmed:
7
4
2022
medline:
2
7
2022
entrez:
6
4
2022
Statut:
ppublish
Résumé
The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Identifiants
pubmed: 35384604
doi: 10.1007/s13238-022-00909-3
pii: 10.1007/s13238-022-00909-3
pmc: PMC8983325
doi:
Substances chimiques
Coronavirus Papain-Like Proteases
EC 3.4.22.2
papain-like protease, SARS-CoV-2
EC 3.4.22.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
940-953Informations de copyright
© 2022. The Author(s).
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