9PVI

SARS-CoV-2 Papain-like Protease (PLpro) in complex with Fragment 47

This is a non-PDB format compatible entry.

Summary for 9PVI

• Entry DOI: 10.2210/pdb9pvi/pdb
• Descriptor: Papain-like protease nsp3, ZINC ION, (7M)-8-methyl-7-(2-methylpyridin-4-yl)-1'-{[(6P)-6-(1H-pyrazol-5-yl)pyridin-2-yl]methyl}-3,4-dihydrospiro[[1]benzopyran-2,4'-piperidine], ... (5 entities in total)
• Functional Keywords: viral protease, inhibitor complex, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 37751.15

Authors

Taylor, A.J.,Fesik, S.W. (deposition date: 2025-08-01, release date: 2026-01-21, Last modification date: 2026-02-04)

Primary citation

Wei, Q.,Taylor, A.J.,Barmade, M.A.,Teuscher, K.B.,Chowdhury, S.,Apakama, C.,Anderson-Daniels, J.,Yongqing, Z.,Schultz, D.C.,Rietz, T.A.,South, T.M.,Crow, M.M.,Zhao, B.,Amporndanai, K.,Sensintaffar, J.L.,Phan, J.,Cherry, S.,Denison, M.,Lee, T.,Fesik, S.W.
Discovery of Fragment-Based Inhibitors of SARS-CoV-2 PL Pro .
J.Med.Chem., 69:1419-1433, 2026

PubMed Abstract: SARS-CoV-2 papain-like protease (PL) plays a key role in viral replication and the host immune response and is a promising target for developing new antiviral treatments. We previously reported a fragment-based screen to identify hits that bind to SARS-CoV-2 PL. Here, we describe the discovery of potent PL inhibitors by optimizing one of these hits via extensive medicinal chemistry guided by multiple X-ray structures of cocomplexes. Lead compound is shown to bind to the S3 and S4 pockets with nanomolar affinity (0.4 μM) and exhibits robust cellular activity and resistance to mutation. This novel class of PL inhibitors can potentially be used as a starting point for the development of inhibitors to combat the emergence of drug-resistant viral strains and future coronavirus outbreaks.

PubMed: 41521555
DOI: 10.1021/acs.jmedchem.5c02832

Experimental method

X-RAY DIFFRACTION (1.8 Å)