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

Proteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. SARS-CoV-2 main protease (M-pro, 3CL(pro)) 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 M-pro inhibitors. Our studies revealed that ebselen derivatives are potent inhibitors of both the proteases. We identified three PLpro and four M-pro 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.

Automated summary

Proteases encoded by SARS-CoV-2, including the main protease (M-pro, 3CL(pro)) and papain-like protease (PLpro), are potential targets for new therapies against COVID-19. Ebselen, an organoselenium anti-inflammatory drug, has been shown to effectively inhibit these proteases and has been evaluated for its antiviral activity. This study screened a collection of ebselen derivatives for inhibitors against SARS-CoV-2 PLpro and M-pro and identified several compounds that are superior to ebselen. Additionally, ebselen was found to inhibit the N7-methyltransferase activity of SARS-CoV-2 nsp14 protein involved in viral RNA cap modification.