Crystal Structure of the Main Protease of Human Coronavirus NL63
Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design.
Sci. Rep. 2016;
15 May 2020 (online)
CoVs are the causative agents responsible for several respiratory syndromes including SARS, MERS, and COVID-19. There are no known treatments for CoV-related ailments currently. The substrate-binding site of the various CoV main proteases (Mpro) have high sequence homology and therefore represent an attractive target for the development of broad-spectrum anti-CoV therapies. In 2016, Yang and co-workers disclosed the crystal structure of the HCoV-NL63 (a human CoV) main protease (MPro) complexed with the covalent inhibitor N3, providing a structural basis for the pharmacological inhibition of CoV Mpro that may have relevance for the ongoing SARS-CoV-2 pandemic.
The Mpro inhibitor N3 is a covalent inhibitor designed as an active site mimic for the TGEV Mpro autoprocessing site. The crystal structure of the HCoV-NL63 Mpro reveals multiple H-bond contacts between residues E166, F129, H163, G142, Q164, and S190. The α,β-unsaturated ester of N3 forms a covalent adduct with cysteine 144, validating the mechanism of inhibition of HCoV-NL63 Mpro by N3. Sequence alignment of the HCoV-NL63 Mpro with six related human and animal CoVs main proteases revealed that they had high sequence homology in the substrate binding site, suggesting that this class of inhibitor may serve as a lead compound for anti-Cov therapeutics.