8UOB

SARS-CoV-2 Papain-like protease (PLpro) with Inhibitor Jun12682

Summary for 8UOB

• Entry DOI: 10.2210/pdb8uob/pdb
• Descriptor: Papain-like protease nsp3, 5-[2-(dimethylamino)ethoxy]-N-{(1R)-1-[(3M,5P)-3-(1-ethyl-1H-pyrazol-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}-2-methylbenzamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: inhibitor, noncovalent, papain-like protease, sars-cov-2, viral protein, viral protein-inhibitor complex, 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: 36907.76

Authors

Ansari, A.,Tan, B.,Ruiz, F.X.,Wang, J.,Arnold, E. (deposition date: 2023-10-19, release date: 2024-04-03, Last modification date: 2024-05-01)

Primary citation

Tan, B.,Zhang, X.,Ansari, A.,Jadhav, P.,Tan, H.,Li, K.,Chopra, A.,Ford, A.,Chi, X.,Ruiz, F.X.,Arnold, E.,Deng, X.,Wang, J.
Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model.
Science, 383:1434-1440, 2024

PubMed Abstract: The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PL) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PL inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PL with the inhibitory constant K values from 13.2 to 88.2 nanomolar. The co-crystal structures of PL with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC from 0.44 to 2.02 micromolar. Oral treatment with Jun12682 improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting that PL inhibitors are promising oral SARS-CoV-2 antiviral candidates.

PubMed: 38547259
DOI: 10.1126/science.adm9724

Experimental method

X-RAY DIFFRACTION (2.52 Å)