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Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors

Author

Listed:
  • Jerzy Osipiuk

    (University of Chicago
    Argonne National Laboratory)

  • Saara-Anne Azizi

    (University of Chicago)

  • Steve Dvorkin

    (University of Chicago)

  • Michael Endres

    (University of Chicago
    Argonne National Laboratory)

  • Robert Jedrzejczak

    (University of Chicago
    Argonne National Laboratory)

  • Krysten A. Jones

    (University of Chicago)

  • Soowon Kang

    (University of Chicago)

  • Rahul S. Kathayat

    (University of Chicago)

  • Youngchang Kim

    (University of Chicago
    Argonne National Laboratory)

  • Vladislav G. Lisnyak

    (University of Chicago)

  • Samantha L. Maki

    (University of Chicago)

  • Vlad Nicolaescu

    (University of Chicago)

  • Cooper A. Taylor

    (University of Chicago)

  • Christine Tesar

    (University of Chicago
    Argonne National Laboratory)

  • Yu-An Zhang

    (University of Chicago)

  • Zhiyao Zhou

    (University of Chicago)

  • Glenn Randall

    (University of Chicago)

  • Karolina Michalska

    (University of Chicago
    Argonne National Laboratory)

  • Scott A. Snyder

    (University of Chicago)

  • Bryan C. Dickinson

    (University of Chicago)

  • Andrzej Joachimiak

    (University of Chicago
    Argonne National Laboratory
    University of Chicago)

Abstract

The pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to expand. Papain-like protease (PLpro) is one of two SARS-CoV-2 proteases potentially targetable with antivirals. PLpro is an attractive target because it plays an essential role in cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex, and disruption of host responses. We report a substantive body of structural, biochemical, and virus replication studies that identify several inhibitors of the SARS-CoV-2 enzyme. We determined the high resolution structure of wild-type PLpro, the active site C111S mutant, and their complexes with inhibitors. This collection of structures details inhibitors recognition and interactions providing fundamental molecular and mechanistic insight into PLpro. All compounds inhibit the peptidase activity of PLpro in vitro, some block SARS-CoV-2 replication in cell culture assays. These findings will accelerate structure-based drug design efforts targeting PLpro to identify high-affinity inhibitors of clinical value.

Suggested Citation

  • Jerzy Osipiuk & Saara-Anne Azizi & Steve Dvorkin & Michael Endres & Robert Jedrzejczak & Krysten A. Jones & Soowon Kang & Rahul S. Kathayat & Youngchang Kim & Vladislav G. Lisnyak & Samantha L. Maki &, 2021. "Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21060-3
    DOI: 10.1038/s41467-021-21060-3
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    Cited by:

    1. Nurbella Sofiana Altu & Cahyo Budiman & Rafida Razali & Ruzaidi Azli Mohd Mokhtar & Khairul Azfar Kamaruzaman, 2022. "Technical Data of In Silico Analysis of the Interaction of Dietary Flavonoid Compounds against Spike-Glycoprotein and Proteases of SARS-CoV-2," Data, MDPI, vol. 7(11), pages 1-24, October.
    2. Brian C. Sanders & Suman Pokhrel & Audrey D. Labbe & Irimpan I. Mathews & Connor J. Cooper & Russell B. Davidson & Gwyndalyn Phillips & Kevin L. Weiss & Qiu Zhang & Hugh O’Neill & Manat Kaur & Jurgen , 2023. "Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Gabriela Dias Noske & Yun Song & Rafaela Sachetto Fernandes & Rod Chalk & Haitem Elmassoudi & Lizbé Koekemoer & C. David Owen & Tarick J. El-Baba & Carol V. Robinson & Glaucius Oliva & Andre Schutzer , 2023. "An in-solution snapshot of SARS-COV-2 main protease maturation process and inhibition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Pawel M. Wydorski & Jerzy Osipiuk & Benjamin T. Lanham & Christine Tesar & Michael Endres & Elizabeth Engle & Robert Jedrzejczak & Vishruth Mullapudi & Karolina Michalska & Krzysztof Fidelis & David F, 2023. "Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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