8YX5
Crystal Structure of SARS CoV-2 Papain-like Protease PLpro-C111S in Complex with GZNL-P35
This is a non-PDB format compatible entry.
Summary for 8YX5
| Entry DOI | 10.2210/pdb8yx5/pdb |
| Descriptor | Papain-like protease nsp3, 5-[(1~{R},5~{S})-3,6-diazabicyclo[3.1.1]heptan-3-yl]-2-methyl-~{N}-[1-(1-methyl-2-oxidanylidene-benzo[cd]indol-6-yl)cyclopropyl]benzamide, ZINC ION, ... (5 entities in total) |
| Functional Keywords | sars cov-2, papain-like proteinase, nsp3, hydrolase |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 2 |
| Total formula weight | 72960.08 |
| Authors | |
| Primary citation | Lu, Y.,Yang, Q.,Ran, T.,Zhang, G.,Li, W.,Zhou, P.,Tang, J.,Dai, M.,Zhong, J.,Chen, H.,He, P.,Zhou, A.,Xue, B.,Chen, J.,Zhang, J.,Yang, S.,Wu, K.,Wu, X.,Tang, M.,Zhang, W.K.,Guo, D.,Chen, X.,Chen, H.,Shang, J. Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19. Nat Commun, 15:10169-10169, 2024 Cited by PubMed Abstract: The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CL), and papain-like protease (PL) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CL inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CL from SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discover a series of novel potent non-covalent PL inhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PL with lead compounds reveal that the residues D164 and Q269 around the S2 site are critical for improving the inhibitor's potency. The lead compound GZNL-P36 not only inhibits SARS-CoV-2 and its variants at the cellular level with EC ranging from 58.2 nM to 306.2 nM, but also inhibits HCoV-NL63 and HCoV-229E with EC of 81.6 nM and 2.66 μM, respectively. Oral administration of the GZNL-P36 results in significantly improved survival and notable reductions in lung viral loads and lesions in SARS-CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PL inhibitors represent a promising SARS-CoV-2 therapy. PubMed: 39580525DOI: 10.1038/s41467-024-54462-0 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.74 Å) |
Structure validation
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