9OR4

Crystal structure of SARS-CoV2 PLpro in complex with a covalent inhibitor

This is a non-PDB format compatible entry.

Summary for 9OR4

• Entry DOI: 10.2210/pdb9or4/pdb
• Descriptor: Replicase polyprotein 1a, ZINC ION, (2S)-3-amino-2-{1-[(1R)-1-(7-ethoxynaphthalen-1-yl)ethyl]piperidin-4-yl}-N-(2-oxo-2-{[(2Z)-4,4,4-trifluorobut-2-en-1-yl]amino}ethyl)propanamide, ... (4 entities in total)
• Functional Keywords: sars-cov2, papain-like protease, covalent inhibitor, anti-viral activity, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 72479.05

Authors

Lye, M.F.,Wang, J.,Namchuk, M.N.,Buhrlage, S.J. (deposition date: 2025-05-21, release date: 2026-02-25)

Primary citation

Sharafi, M.,Teh, W.P.,Green, J.,Charifson, P.S.,Wang, J.,Pemberton, O.A.,Nevins, A.M.,Lye, M.,Liu, X.,Varca, A.C.,Owen, C.D.,Morsheimer, K.,Wacquiez, A.,Dawson, C.,Steuber, C.,Smith, J.,Girardi, N.M.,Magin, R.S.,Marto, J.A.,Saeed, M.,Davey, R.A.,Hardee, D.,Ng, T.I.,Namchuk, M.N.,Buhrlage, S.J.
Structure-Guided Design of Potent and Selective Covalent Inhibitors Targeting the SARS-CoV-2 Papain-like Protease.
J.Med.Chem., 69:2197-2214, 2026

PubMed Abstract: The COVID-19 pandemic led to numerous initiatives to create antiviral medications and vaccines for the treatment and prevention of infections. However, the need remains for new therapies with distinct mechanisms of action from current treatment of COVID-19 infections as well as for future pandemic preparedness. SARS-CoV-2 papain-like protease (PLpro) is a cysteine protease that cleaves the viral polyprotein and possesses deubiquitylase (DUB) and deISGylase activity that can act on host proteins. Here, we report the structure-guided development of covalent inhibitors of SARS-CoV-2 PLpro that possess low nanomolar to subnanomolar antiviral activity in cell assays and inhibit viral replication in a mouse model of SARS-CoV-2 infection. The most potent inhibitors contain -propargylamide electrophiles, a relatively inert warhead not typically featured in covalent protease inhibitors. These findings provide a foundation for further discovery and optimization of covalent PLpro inhibitors that could lead to future antiviral therapeutics.

PubMed: 41557701
DOI: 10.1021/acs.jmedchem.5c01973

Experimental method

X-RAY DIFFRACTION (2.43 Å)