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Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease.

ABSTRACT: SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host's innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections.

SUBMITTER: Srinivasan V

PROVIDER: S-EPMC9366811 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease.

Srinivasan Vasundara V Brognaro Hévila H Prabhu Prince R PR de Souza Edmarcia Elisa EE Günther Sebastian S Reinke Patrick Y A PYA Lane Thomas J TJ Ginn Helen H Han Huijong H Ewert Wiebke W Sprenger Janina J Koua Faisal H M FHM Falke Sven S Werner Nadine N Andaleeb Hina H Ullah Najeeb N Franca Bruno Alves BA Wang Mengying M Barra Angélica Luana C ALC Perbandt Markus M Schwinzer Martin M Schmidt Christina C Brings Lea L Lorenzen Kristina K Schubert Robin R Machado Rafael Rahal Guaragna RRG Candido Erika Donizette ED Oliveira Danielle Bruna Leal DBL Durigon Edison Luiz EL Niebling Stephan S Garcia Angelica Struve AS Yefanov Oleksandr O Lieske Julia J Gelisio Luca L Domaracky Martin M Middendorf Philipp P Groessler Michael M Trost Fabian F Galchenkova Marina M Mashhour Aida Rahmani AR Saouane Sofiane S Hakanpää Johanna J Wolf Markus M Alai Maria Garcia MG Turk Dusan D Pearson Arwen R AR Chapman Henry N HN Hinrichs Winfried W Wrenger Carsten C Meents Alke A Betzel Christian C

Communications biology 20220811 1

SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host's innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compo ...[more]

PMID: 35953531

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Project description:Over 10 years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (SARS-CoV) emerged from the Guangdong Province of China. Despite the fact that the SARS-CoV pandemic infected over 8500 individuals, claimed over 800 lives and cost billions of dollars in economic loss worldwide, there still are no clinically approved antiviral drugs, vaccines or monoclonal antibody therapies to treat SARS-CoV infections. The recent emergence of the deadly human coronavirus that causes Middle East respiratory syndrome (MERS-CoV) is a sobering reminder that new and deadly coronaviruses can emerge at any time with the potential to become pandemics. Therefore, the continued development of therapeutic and prophylactic countermeasures to potentially deadly coronaviruses is warranted. The coronaviral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), are attractive antiviral drug targets because they are essential for coronaviral replication. Although the primary function of PLpro and 3CLpro are to process the viral polyprotein in a coordinated manner, PLpro has the additional function of stripping ubiquitin and ISG15 from host-cell proteins to aid coronaviruses in their evasion of the host innate immune responses. Therefore, targeting PLpro with antiviral drugs may have an advantage in not only inhibiting viral replication but also inhibiting the dysregulation of signaling cascades in infected cells that may lead to cell death in surrounding, uninfected cells. This review provides an up-to-date discussion on the SARS-CoV papain-like protease including a brief overview of the SARS-CoV genome and replication followed by a more in-depth discussion on the structure and catalytic mechanism of SARS-CoV PLpro, the multiple cellular functions of SARS-CoV PLpro, the inhibition of SARS-CoV PLpro by small molecule inhibitors, and the prospect of inhibiting papain-like protease from other coronaviruses. This paper forms part of a series of invited articles in Antiviral Research on "From SARS to MERS: 10years of research on highly pathogenic human coronaviruses."

Dataset Information

Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease.

Publications

Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease.

Similar Datasets

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