Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2
- Klemm, 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.
- Noort, G.J.V. van
- Geurink, P.P.
- Ovaa, H.
- Newman, J.
- Riboldi-Tunnicliffe, A.
- Czabotar, P.E.
- Mitchell, J.P.
- Feltham, R.
- Lechtenberg, B.C.
- Lowes, K.N.
- Dewson, G.
- Pellegrini, M.
- Lessene, G.
- Komander, D.
DOIAbstract
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 counter...
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