8EUA

Structure of SARS-CoV2 PLpro bound to a covalent inhibitor

Summary for 8EUA

• Entry DOI: 10.2210/pdb8eua/pdb
• Descriptor: Papain-like protease nsp3, methyl 4-{2-[3-(2-{[(1R)-1-(naphthalen-1-yl)ethyl]carbamoyl}phenyl)propanoyl]hydrazinyl}-4-oxobutanoate, ZINC ION, ... (5 entities in total)
• Functional Keywords: plpro, sars-cov2, covalent inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2, COVID-19 virus)
• Total number of polymer chains: 1
• Total formula weight: 36937.99

Authors

Mathews, I.I.,Pokhrel, S.,Wakatsuki, S. (deposition date: 2022-10-18, release date: 2023-04-05, Last modification date: 2024-11-06)

Primary citation

Sanders, B.C.,Pokhrel, S.,Labbe, A.D.,Mathews, I.I.,Cooper, C.J.,Davidson, R.B.,Phillips, G.,Weiss, K.L.,Zhang, Q.,O'Neill, H.,Kaur, M.,Schmidt, J.G.,Reichard, W.,Surendranathan, S.,Parvathareddy, J.,Phillips, L.,Rainville, C.,Sterner, D.E.,Kumaran, D.,Andi, B.,Babnigg, G.,Moriarty, N.W.,Adams, P.D.,Joachimiak, A.,Hurst, B.L.,Kumar, S.,Butt, T.R.,Jonsson, C.B.,Ferrins, L.,Wakatsuki, S.,Galanie, S.,Head, M.S.,Parks, J.M.
Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2.
Nat Commun, 14:1733-1733, 2023

PubMed Abstract: Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we design a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibits PLpro with k/K = 9,600 M s, achieves sub-μM EC values against three SARS-CoV-2 variants in mammalian cell lines, and does not inhibit a panel of human deubiquitinases (DUBs) at >30 μM concentrations of inhibitor. An X-ray co-crystal structure of the compound bound to PLpro validates our design strategy and establishes the molecular basis for covalent inhibition and selectivity against structurally similar human DUBs. These findings present an opportunity for further development of covalent PLpro inhibitors.

PubMed: 36977673
DOI: 10.1038/s41467-023-37254-w

Experimental method

X-RAY DIFFRACTION (3.1 Å)