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10.15252/embj.2020106275

http://scihub22266oqcxt.onion/10.15252/embj.2020106275
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32845033!7461020!32845033
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suck abstract from ncbi

pmid32845033
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  • Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2 #MMPMID32845033
  • Klemm T; Ebert G; Calleja DJ; Allison CC; Richardson LW; Bernardini JP; Lu BG; Kuchel NW; Grohmann C; Shibata Y; Gan ZY; Cooney JP; Doerflinger M; Au AE; Blackmore TR; van der Heden van Noort GJ; Geurink PP; Ovaa H; Newman J; Riboldi-Tunnicliffe A; Czabotar PE; Mitchell JP; Feltham R; Lechtenberg BC; Lowes KN; Dewson G; Pellegrini M; Lessene G; Komander D
  • EMBO J 2020[Sep]; 39 (18): e106275 PMID32845033show ga
  • 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.
  • |Animals[MESH]
  • |Antiviral Agents/*pharmacology[MESH]
  • |Binding Sites[MESH]
  • |Chlorocebus aethiops[MESH]
  • |Coronavirus 3C Proteases/*antagonists & inhibitors/chemistry/genetics/*metabolism[MESH]
  • |Crystallography, X-Ray[MESH]
  • |Cytokines/genetics[MESH]
  • |Drug Evaluation, Preclinical/methods[MESH]
  • |Drug Repositioning[MESH]
  • |Fluorescence Polarization[MESH]
  • |HEK293 Cells[MESH]
  • |Humans[MESH]
  • |Kinetics[MESH]
  • |Models, Molecular[MESH]
  • |Protease Inhibitors/pharmacology[MESH]
  • |Protein Conformation[MESH]
  • |SARS-CoV-2/chemistry/genetics/*metabolism[MESH]
  • |Ubiquitin/*metabolism[MESH]
  • |Ubiquitins/genetics[MESH]
  • |Vero Cells[MESH]


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  • suck abstract from ncbi

    e106275 18.39 2020