SARS-CoV is the coronavirus (CoV) that causes severe acute respiratory syndrome (SARS), including not only SARS, but also Middle East respiratory syndrome (MERS) and SARS-CoV-2 (the cause of COVID-19). The 3C-like protease (3CLpro) is the main protease found in coronaviruses. The 3CL protease corresponds to coronavirus nonstructural protein 5 (nsp5). The 3CLpro of SARS-CoV-2 is an excellent target for COVID-19 antiviral drug development. Therefore, 3CLpro is essential for viral replication and has cleavage specificity distinct from human proteases. SARS-CoV-2 3CLpro consists of three domains: Domain I (residues 10-99) and II (residues 100-182) resemble picornavirus 3C proteases and chymotrypsin. In addition, the structure of 3CLpro, highly conserved among coronaviruses, which indicates that the development of pan-coronavirus inhibitors against 3CLpro is feasible.

GRL-0496 is a potent chloropyridyl ester-derived SARS-CoV 3C-like protease (3CLpro) inhibitor. In addition, GRL-0496 shows SARS-CoV antiviral activity. Molecular docking studies show that GRL-0496 with a 5-chloropyridinyl ester at position 4 of the indole ring is the most potent inhibitor. Moreover, the indole group of GRL-0496, located near the more hydrophobic S2 pocket, with the indole nitrogen likely interacting with the imidazole group of His-41. Recently, this compound is also active against SARS-CoV-2. Furthermore, GRL-0496 also shows significant inhibitory activity against SARS-CoV-2 3CLpro in cells in a cell-based luciferase complementation assay.

To sum up, GRL-0496 is a potent SARS-CoV 3CLpro inhibitor, showing potent activity in both enzyme inhibitory and antiviral assays.


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[2] Jonathan M O Rawson, et al. Viruses. 2021 Jan 24;13(2):173.