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dc.contributor.authorKlemm, T
dc.contributor.authorEbert, G
dc.contributor.authorCalleja, DJ
dc.contributor.authorAllison, CC
dc.contributor.authorRichardson, LW
dc.contributor.authorBernardini, JP
dc.contributor.authorLu, BGC
dc.contributor.authorKuchel, NW
dc.contributor.authorGrohmann, C
dc.contributor.authorShibata, Y
dc.contributor.authorGan, ZY
dc.contributor.authorCooney, JP
dc.contributor.authorDoerflinger, M
dc.contributor.authorAu, AE
dc.contributor.authorBlackmore, TR
dc.contributor.authorvan der Heden van Noort, GJ
dc.contributor.authorGeurink, PP
dc.contributor.authorOvaa, H
dc.contributor.authorNewman, J
dc.contributor.authorRiboldi-Tunnicliffe, A
dc.contributor.authorCzabotar, PE
dc.contributor.authorMitchell, JP
dc.contributor.authorFeltham, R
dc.contributor.authorLechtenberg, BC
dc.contributor.authorLowes, KN
dc.contributor.authorDewson, G
dc.contributor.authorPellegrini, M
dc.contributor.authorLessene, G
dc.contributor.authorKomander, D
dc.identifier.citationKlemm, T., Ebert, G., Calleja, D. J., Allison, C. C., Richardson, L. W., Bernardini, J. P., Lu, B. G. C., Kuchel, N. W., Grohmann, C., Shibata, Y., Gan, Z. Y., Cooney, J. P., Doerflinger, M., Au, A. E., Blackmore, T. R., van der Heden van Noort, G. J., Geurink, P. P., Ovaa, H., Newman, J. ,... Komander, D. (2020). Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2. EMBO JOURNAL, 39 (18),
dc.description.abstractThe 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.
dc.titleMechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2
dc.typeJournal Article
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.source.titleThe EMBO Journal
melbourne.openaccess.statusPublished version
melbourne.contributor.authorLessene, Guillaume
melbourne.contributor.authorAllison, Cody
melbourne.contributor.authorEbert, Gregor
melbourne.contributor.authorLowes, Kym
melbourne.contributor.authorDewson, Grant
melbourne.contributor.authorPellegrini, Marc
melbourne.contributor.authorAu, Amanda
melbourne.contributor.authorFeltham, Rebecca
melbourne.contributor.authorDoerflinger, Marcel
melbourne.contributor.authorLechtenberg, Bernhard
melbourne.contributor.authorCzabotar, Peter
melbourne.accessrightsAccess this item via the Open Access location

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