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Publication Abstract from PubMed

The main protease (M(pro)) of coronaviruses participates in viral replication, serving as a hot target for drug design. GC376 is able to effectively inhibit the activity of M(pro), which is due to nucleophilic addition of GC376 by binding covalently with Cys145 in M(pro) active site. Here, we used fluorescence resonance energy transfer (FRET) assay to analyze the IC(50) values of GC376 against M(pro)s from six different coronaviruses (SARS-CoV-2, HCoV-229E, HCoV-HUK1, MERS-CoV, SARS-CoV, HCoV-NL63) and five M(pro) mutants (G15S, M49I, K90R, P132H, S46F) from SARS-CoV-2 variants. The results showed that GC376 displays effective inhibition to various coronaviral M(pro)s and SARS-CoV-2 M(pro) mutants. In addition, the crystal structures of SARS-CoV-2 M(pro) (wide type)-GC376, SARS-CoV M(pro)-GC376, MERS-CoV M(pro)-GC376, and SARS-CoV-2 M(pro) mutants (G15S, M49I, S46F, K90R, and P132H)-GC376 complexes were solved. We found that GC376 is able to fit into the active site of M(pro)s from different coronaviruses and different SARS-CoV-2 variants properly. Detailed structural analysis revealed key molecular determinants necessary for inhibition and illustrated the binding patterns of GC376 to these different M(pro)s. In conclusion, we not only proved the inhibitory activity of GC376 against different M(pro)s including SARS-CoV-2 M(pro) mutants, but also revealed the molecular mechanism of inhibition by GC376, which will provide scientific guidance for the development of broad-spectrum drugs against SARS-CoV-2 as well as other coronaviruses.

Structural Basis for Coronaviral Main Proteases Inhibition by the 3CLpro Inhibitor GC376.,Lin C, Zhu Z, Jiang H, Zou X, Zeng X, Wang J, Zeng P, Li W, Zhou X, Zhang J, Wang Q, Li J J Mol Biol. 2024 Mar 15;436(6):168474. doi: 10.1016/j.jmb.2024.168474. Epub 2024 , Feb 2. PMID:38311236^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.