9CEH

SARS-CoV Papain-like Protease in complex with an inhibitor

This is a non-PDB format compatible entry.

Summary for 9CEH

• Entry DOI: 10.2210/pdb9ceh/pdb
• Descriptor: Papain-like protease nsp3, N-[(2R)-1-(naphthalen-1-yl)propan-2-yl]-2-[3-oxo-3-(2-{4-oxo-4-[(pyridin-3-yl)amino]butanoyl}hydrazin-1-yl)propyl]benzamide (2 entities in total)
• Functional Keywords: papain-like protease, plpro, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus
• Total number of polymer chains: 1
• Total formula weight: 35369.03

Authors

Chua, T.K.,Song, Y. (deposition date: 2024-06-26, release date: 2025-12-03)

Primary citation

Garad, D.N.,Li, X.,Chua, T.K.,Moku, B.K.,Mishra, C.B.,Song, Y.
Targeting the S1' Pocket of SARS-CoV‐2 Papain-Like Protease Yields Highly Potent Inhibitors.
Acs Med.Chem.Lett., 16:2280-2285, 2025

PubMed Abstract: SARS-CoV-2 and -CoV viruses are major human pathogens. Due to their zoonotic nature as well as emerging drug-resistant mutations, new antivirals are needed. The viral papain-like protease (PLpro) is a drug target. Targeting the mostly hydrophobic S1' pocket of PLpro, we designed and synthesized 21 amide compounds, among which several highly potent PLpro inhibitors were identified with IC values as low as 16 nM. Structure-activity relationship analysis showed that an electron-deficient pyridine-containing amide group can significantly enhance the activity. The X-ray structure of the PLpro-compound complex revealed that the pyridine ring has favorable π-π and electrostatic interactions with the electron-rich indole group of Trp106. Compound is inactive against human ubiquitin-specific protease 7 and noncytotoxic to mammalian cells, showing excellent selectivity. It can potently inhibit cellular replication of SARS-CoV-2 with an EC of 96 nM. These results show that compound represents a novel pharmaceutical lead for further drug development.

PubMed: 41256988
DOI: 10.1021/acsmedchemlett.5c00482

Experimental method

X-RAY DIFFRACTION (3.25 Å)