8UUG
SARS-CoV-2 papain-like protease (PLpro) with inhibitor Jun12303
Summary for 8UUG
| Entry DOI | 10.2210/pdb8uug/pdb |
| Descriptor | Papain-like protease nsp3, N-[(1R)-1-{(3M,5M)-3-[1-(difluoromethyl)-1H-pyrazol-4-yl]-5-[1-(methoxymethyl)-1H-pyrazol-4-yl]phenyl}ethyl]-5-[2-(dimethylamino)ethoxy]-2-methylbenzamide, GLYCEROL, ... (7 entities in total) |
| Functional Keywords | sars cov-2 papain-like protease, 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 | 37116.37 |
| Authors | Ansari, A.,Tan, B.,Ruiz, F.X.,Arnold, E.,Wang, J. (deposition date: 2023-11-01, 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 Cited by 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: 38547259DOI: 10.1126/science.adm9724 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.74 Å) |
Structure validation
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