9Z0D

SARS-CoV-2 Papain-like Protease (PLpro) in complex with Fragment 41

This is a non-PDB format compatible entry.

Summary for 9Z0D

• Entry DOI: 10.2210/pdb9z0d/pdb
• Descriptor: Papain-like protease nsp3, ZINC ION, N'-[3-(2-{[(7M)-8-methyl-7-(2-methylpyridin-4-yl)-3,4-dihydrospiro[[1]benzopyran-2,4'-piperidin]-1'-yl]methyl}pyridin-3-yl)propanoyl]-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-oxobutanehydrazide, ... (4 entities in total)
• Functional Keywords: viral protease, inhibitor, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 4
• Total formula weight: 146932.12

Authors

Taylor, A.J. (deposition date: 2025-10-31, release date: 2026-02-18, Last modification date: 2026-02-25)

Primary citation

Wei, Q.,Taylor, A.J.,Miriyala, N.,Barmade, M.A.,Gentry, Z.O.,Anderson-Daniels, J.,Teuscher, K.B.,Crow, M.M.,Apakama, C.,South, T.M.,Rietz, T.A.,Amporndanai, K.,Phan, J.,Sensintaffar, J.L.,Denison, M.,Lee, T.,Fesik, S.W.
Discovery of Spiro[chromane-2,4'-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease.
J.Med.Chem., 69:3588-3608, 2026

PubMed Abstract: The papain-like protease (PL) plays a key role in SARS-CoV-2 replication and represents a promising target for the development of new antiviral therapies. Previous efforts to develop fragment-derived inhibitors of PL led to the identification of a novel class of spiro[chromane-2,4'-piperidin]-4-one inhibitors exemplified by lead compound . High-resolution covalent cocrystal structures and molecular dynamics simulations were utilized to guide the development of a series of low-nanomolar irreversible PL inhibitors, with lead compound demonstrating strong enzymatic inhibition (IC = 0.059 μM at = 60 min) and antiviral activity in A549 cells (EC = 2.1 μM at 48 hpi). This novel class of inhibitors represents a promising avenue for the development of therapeutics to overcome the potential of drug-resistant viral strains and future coronavirus outbreaks.

PubMed: 41629155
DOI: 10.1021/acs.jmedchem.5c03704

Experimental method

X-RAY DIFFRACTION (1.65 Å)