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Ebselen derivatives inhibit SARS-CoV-2 replication by inhibition of its essential proteins: PLpro and Mpro proteases, and nsp14 guanine N7-methyltransferase

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dc.abstract.enProteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. SARS-CoV-2 main protease (Mpro, 3CLpro) and papain-like protease (PLpro) are responsible for viral polyprotein cleavage—a process crucial for viral survival and replication. Recently it was shown that 2-phenylbenzisoselenazol-3(2H)-one (ebselen), an organoselenium anti-inflammatory small-molecule drug, is a potent, covalent inhibitor of both the proteases and its potency was evaluated in enzymatic and antiviral assays. In this study, we screened a collection of 34 ebselen and ebselen diselenide derivatives for SARS-CoV-2 PLpro and Mpro inhibitors. Our studies revealed that ebselen derivatives are potent inhibitors of both the proteases. We identified three PLpro and four Mpro inhibitors superior to ebselen. Independently, ebselen was shown to inhibit the N7-methyltransferase activity of SARS-CoV-2 nsp14 protein involved in viral RNA cap modification. Hence, selected compounds were also evaluated as nsp14 inhibitors. In the second part of our work, we employed 11 ebselen analogues—bis(2-carbamoylaryl)phenyl diselenides—in biological assays to evaluate their anti-SARS-CoV-2 activity in Vero E6 cells. We present their antiviral and cytoprotective activity and also low cytotoxicity. Our work shows that ebselen, its derivatives, and diselenide analogues constitute a promising platform for development of new antivirals targeting the SARS-CoV-2 virus.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorJemielity, Jacek
dc.contributor.authorDrag, Marcin
dc.contributor.authorHilgenfeld, Rolf
dc.contributor.authorWeber, Jan
dc.contributor.authorOlsen, Shaun K.
dc.contributor.authorKęsik-Brodacka, Małgorzata
dc.contributor.authorNayak, Digant
dc.contributor.authorLv, Zongyang
dc.contributor.authorSun, Xinyuanyuan
dc.contributor.authorZhang, Linlin
dc.contributor.authorKasprzyk, Renata
dc.contributor.authorZgarbova, Michala
dc.contributor.authorKaleta, Rafał
dc.contributor.authorBurda-Grabowska, Małgorzata
dc.contributor.authorGiurg, Mirosław
dc.contributor.authorGranda, Jarosław
dc.contributor.authorOlech, Kamila
dc.contributor.authorRut, Wioletta
dc.contributor.authorZmudzinski, Mikolaj
dc.date.accessioned2024-01-24T22:25:13Z
dc.date.available2024-01-24T22:25:13Z
dc.date.copyright2023-06-06
dc.date.issued2023
dc.description.accesstimeAT_PUBLICATION
dc.description.financePublikacja bezkosztowa
dc.description.number1
dc.description.versionFINAL_PUBLISHED
dc.description.volume13
dc.identifier.doi10.1038/S41598-023-35907-W
dc.identifier.issn2045-2322
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/105629
dc.identifier.weblinkhttps://www.nature.com/articles/s41598-023-35907-w.pdf
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofScientific Reports
dc.rightsCC-BY
dc.sciencecloudnosend
dc.titleEbselen derivatives inhibit SARS-CoV-2 replication by inhibition of its essential proteins: PLpro and Mpro proteases, and nsp14 guanine N7-methyltransferase
dc.typeJournalArticle
dspace.entity.typePublication