9DNU

SARS-CoV-2 papain-like protease (PLpro) with inhibitor Jun13296

This is a non-PDB format compatible entry.

Summary for 9DNU

• Entry DOI: 10.2210/pdb9dnu/pdb
• Descriptor: Papain-like protease nsp3, 2-methyl-5-[(1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-N-{(1R)-1-[(2P)-2-(1-methyl-1H-pyrazol-4-yl)quinolin-4-yl]ethyl}benzamide, ACETATE ION, ... (7 entities in total)
• Functional Keywords: sars cov-2 papain like protease (plpro), complex, inhibitor, jun13296, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, 2019-nCoV, COVID-19 virus)
• Total number of polymer chains: 1
• Total formula weight: 37224.59

Authors

Ansari, A.,Jadhav, P.,Arnold, E.,Ruiz, F.X.,Wang, J. (deposition date: 2024-09-18, release date: 2025-01-22, Last modification date: 2025-02-26)

Primary citation

Jadhav, P.,Liang, X.,Ansari, A.,Tan, B.,Tan, H.,Li, K.,Chi, X.,Ford, A.,Ruiz, F.X.,Arnold, E.,Deng, X.,Wang, J.
Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates.
Nat Commun, 16:1604-1604, 2025

PubMed Abstract: The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents the systematic design of quinoline-containing SARS-CoV-2 papain-like protease (PL) inhibitors as potential oral antiviral drug candidates. By leveraging the recently discovered Val70 binding site in PL, we designed a series of quinoline analogs demonstrating potent PL inhibition and antiviral activity. Notably, the X-ray crystal structures of 6 lead compounds reveal that the 2-aryl substitution can occupy either the Val70 site as expected or the BL2 groove in a flipped orientation. The in vivo lead Jun13296 exhibits favorable pharmacokinetic properties and potent inhibition against SARS-CoV-2 variants and nirmatrelvir-resistant mutants. In a mouse model of SARS-CoV-2 infection, oral treatment with Jun13296 significantly improves survival, reduces body weight loss and lung viral titers, and prevents lung tissue damage. These results underscore the potential of quinoline PL inhibitors as promising oral SARS-CoV-2 antiviral candidates, instilling hope for the future of SARS-CoV-2 treatment.

PubMed: 39948104
DOI: 10.1038/s41467-025-56902-x

Experimental method

X-RAY DIFFRACTION (2.3 Å)