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

DOI: 10.1038/s42003-022-03737-7 DOI Help

Authors: Vasundara Srinivasan (Universität Hamburg) , Hévila Brognaro (Universität Hamburg) , Prince R. Prabhu (Universität Hamburg) , Edmarcia Elisa De Souza (University of São Paulo) , Sebastian Günther (Deutsches Elektronen Synchrotron DESY) , Patrick Y. A. Reinke (Deutsches Elektronen Synchrotron DESY) , Thomas J. Lane (Universität Hamburg; Deutsches Elektronen Synchrotron DESY) , Helen Ginn (Diamond Light Source) , Huijong Han (European XFEL) , Wiebke Ewert (Deutsches Elektronen Synchrotron DESY) , Janina Sprenger (Deutsches Elektronen Synchrotron DESY) , Faisal H. M. Koua (Deutsches Elektronen Synchrotron DESY) , Sven Falke (Universität Hamburg; Deutsches Elektronen Synchrotron DESY) , Nadine Werner (Universität Hamburg) , Hina Andaleeb (Universität Hamburg; Bahauddin Zakariya University Multan) , Najeeb Ullah (Universität Hamburg; Bahauddin Zakariya University Multan) , Bruno Alves Franca (Universität Hamburg) , Mengying Wang (Universität Hamburg) , Angélica Luana C. Barra (Universität Hamburg; University of São Paulo) , Markus Perbandt (Universität Hamburg) , Martin Schwinzer (Universität Hamburg) , Christina Schmidt (European XFEL) , Lea Brings (European XFEL) , Kristina Lorenzen (European XFEL) , Robin Schubert (European XFEL) , Rafael Rahal Guaragna Machado (University of São Paulo) , Erika Donizette Candido (University of São Paulo) , Danielle Bruna Leal Oliveira (University of São Paulo; Hospital Israelita Albert Einstein) , Edison Luiz Durigon (University of São Paulo; Scientific Platform Pasteur USP) , Stephan Niebling (European Molecular Biology Laboratory Hamburg) , Angelica Struve Garcia (European Molecular Biology Laboratory) , Oleksandr Yefanov (Deutsches Elektronen Synchrotron DESY) , Julia Lieske (Deutsches Elektronen Synchrotron DESY) , Luca Gelisio (Deutsches Elektronen Synchrotron DESY) , Martin Domaracky (Deutsches Elektronen Synchrotron DESY) , Philipp Middendorf (Deutsches Elektronen Synchrotron DESY) , Michael Groessler (Deutsches Elektronen Synchrotron DESY) , Fabian Trost (Deutsches Elektronen Synchrotron DESY) , Marina Galchenkova (Deutsches Elektronen Synchrotron DESY) , Aida Rahmani Mashhour (Deutsches Elektronen Synchrotron DESY) , Sofiane Saouane (Deutsches Elektronen Synchrotron DESY) , Johanna Hakanpää (Deutsches Elektronen Synchrotron DESY) , Markus Wolf (Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP)) , Maria Garcia Alai (European Molecular Biology Laboratory Hamburg) , Dusan Turk (Jozef Stefan Institute; Centre of excellence for Integrated Approaches in Chemistry and Biology of Proteins (CIPKEBIP)) , Arwen R. Pearson (Universität Hamburg) , Henry N. Chapman (Universität Hamburg; Deutsches Elektronen Synchrotron DESY) , Winfried Hinrichs (Universität Greifswald) , Carsten Wrenger (University of São Paulo) , Alke Meents (Deutsches Elektronen Synchrotron DESY) , Christian Betzel (Universität Hamburg)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Biology , VOL 5

State: Published (Approved)
Published: August 2022

Open Access Open Access

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.

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Facility: P11 at PETRA III/DESY

Added On: 14/08/2022 11:34


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

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