Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS CoV 2 3CL protease in vitro
Human infections with severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) cause coronavirus disease 19 (COVID 19) and there is currently no cure. The 3C like protease (3CLpro) a highly conserved protease indispensable for replication of coronaviruses, is a promising target for development of broad spectrum antiviral drugs. To advance the speed of drug discovery and development, we investigated the inhibition of SARS CoV 2 3CLpro by natural products derived from Chinese traditional medicines. Baicalin and baicalein were identified as the first non covalent, non peptidomimetic inhibitors of SARS CoV 2 3CLpro and exhibited potent antiviral activities in a cell based system. Remarkably, the binding mode of baicalein with SARS CoV 2 3CLpro determined by X ray protein crystallography is distinctly different from those of known inhibitors. Baicalein is perfectly ensconced in the core of the substrate binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti coronaviral drugs.