Your browser doesn't support javascript.
loading
Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2.
Klemm, Theresa; Ebert, Gregor; Calleja, Dale J; Allison, Cody C; Richardson, Lachlan W; Bernardini, Jonathan P; Lu, Bernadine Gc; Kuchel, Nathan W; Grohmann, Christoph; Shibata, Yuri; Gan, Zhong Yan; Cooney, James P; Doerflinger, Marcel; Au, Amanda E; Blackmore, Timothy R; van der Heden van Noort, Gerbrand J; Geurink, Paul P; Ovaa, Huib; Newman, Janet; Riboldi-Tunnicliffe, Alan; Czabotar, Peter E; Mitchell, Jeffrey P; Feltham, Rebecca; Lechtenberg, Bernhard C; Lowes, Kym N; Dewson, Grant; Pellegrini, Marc; Lessene, Guillaume; Komander, David.
Affiliation
  • Klemm T; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Ebert G; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Calleja DJ; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Allison CC; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Richardson LW; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Bernardini JP; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Lu BG; Department of Biochemistry and Molecular Biology, Michael Smith Laboratories University of British Columbia, Vancouver, BC, Canada.
  • Kuchel NW; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Grohmann C; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Shibata Y; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Gan ZY; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Cooney JP; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Doerflinger M; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Au AE; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Blackmore TR; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • van der Heden van Noort GJ; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Geurink PP; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, The Netherlands.
  • Ovaa H; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, The Netherlands.
  • Newman J; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, The Netherlands.
  • Riboldi-Tunnicliffe A; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program, Parkville, Vic., Australia.
  • Czabotar PE; Australian Synchrotron, ANSTO, Clayton, Vic., Australia.
  • Mitchell JP; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Feltham R; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Lechtenberg BC; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Lowes KN; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Dewson G; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Pellegrini M; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Lessene G; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
  • Komander D; The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Vic., Australia.
EMBO J ; 39(18): e106275, 2020 09 15.
Article in En | MEDLINE | ID: mdl-32845033
The SARS-CoV-2 coronavirus encodes an essential papain-like protease domain as part of its non-structural protein (nsp)-3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin-like ISG15 protein modifications as well as, with lower activity, Lys48-linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin-binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non-covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self-processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS-CoV-2 infection model.
Subject(s)
Key words
Fulltext
Add to My VHL
Print
XML
PubMed Links
Search on Google

Full text: 1 Database: MEDLINE Main subject: Antiviral Agents / Ubiquitin / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: EMBO J Year: 2020 Type: Article Affiliation country: Australia
Fulltext
Add to My VHL
Print
XML
PubMed Links
Search on Google

Full text: 1 Database: MEDLINE Main subject: Antiviral Agents / Ubiquitin / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: EMBO J Year: 2020 Type: Article Affiliation country: Australia