9G0H

Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the noncovalently bound inhibitor C5N17A

This is a non-PDB format compatible entry.

Summary for 9G0H

• Entry DOI: 10.2210/pdb9g0h/pdb
• Descriptor: 3C-like proteinase nsp5, DIMETHYL SULFOXIDE, [(1~{S},5~{R})-8-[(~{S})-(3-fluorophenyl)-[1-(2-thiophen-3-ylethyl)-1,2,3-triazol-4-yl]methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(5-methylpyridin-3-yl)methanone, ... (6 entities in total)
• Functional Keywords: main protease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 68540.02

Authors

Yang, C.-C.,Strater, N.,Sylvester, K.,Muller, C.E.,Yang, M.,Lee, M.K.,Gao, S.,Song, L.,Liu, X.,Kim, M.,Zhan, P. (deposition date: 2024-07-08, release date: 2025-07-02)

Primary citation

Yang, M.,Lee, M.K.,Gao, S.,Song, L.,Jang, H.Y.,Jo, I.,Yang, C.C.,Sylvester, K.,Ko, C.,Wang, S.,Ye, B.,Tang, K.,Li, J.,Gu, M.,Muller, C.E.,Strater, N.,Liu, X.,Kim, M.,Zhan, P.
Miniaturized Modular Click Chemistry-enabled Rapid Discovery of Unique SARS-CoV-2 M pro Inhibitors With Robust Potency and Drug-like Profile.
Adv Sci, 11:e2404884-e2404884, 2024

PubMed Abstract: The COVID-19 pandemic has required an expeditious advancement of innovative antiviral drugs. In this study, focused compound libraries are synthesized in 96- well plates utilizing modular click chemistry to rapidly discover potent inhibitors targeting the main protease (M) of SARS-CoV-2. Subsequent direct biological screening identifies novel 1,2,3-triazole derivatives as robust M inhibitors with high anti-SARS-CoV-2 activity. Notably, C5N17B demonstrates sub-micromolar M inhibitory potency (IC = 0.12 µM) and excellent antiviral activity in Calu-3 cells determined in an immunofluorescence-based antiviral assay (EC = 0.078 µM, no cytotoxicity: CC > 100 µM). C5N17B shows superior potency to nirmatrelvir (EC = 1.95 µM) and similar efficacy to ensitrelvir (EC = 0.11 µM). Importantly, this compound displays high antiviral activities against several SARS-CoV-2 variants (Gamma, Delta, and Omicron, EC = 0.13 - 0.26 µM) and HCoV-OC43, indicating its broad-spectrum antiviral activity. It is worthy that C5N17B retains antiviral activity against nirmatrelvir-resistant strains with T21I/E166V and L50F/E166V mutations in M (EC = 0.26 and 0.15 µM, respectively). Furthermore, C5N17B displays favorable pharmacokinetic properties. Crystallography studies reveal a unique, non-covalent multi-site binding mode. In conclusion, these findings substantiate the potential of C5N17B as an up-and-coming drug candidate targeting SARS-CoV-2 M for clinical therapy.

PubMed: 39319611
DOI: 10.1002/advs.202404884

Experimental method

X-RAY DIFFRACTION (1.65 Å)