The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CL pro ) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CL pro . Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CL pro s, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands. SARS-CoV-2 3CL protease (3CL pro ) is essential for coronavirus replication and of great interest as an antiviral drug target. Here, the authors show that the naturally occurring flavonoid myricetin is a non-peptidomimetic and covalent inhibitor of 3CL pro , and they solve crystal structures of 3CL pro with myricetin and derivatives, which reveal that the pyrogallol group covalently modifies the catalytic cysteine.
【저자키워드】 viral infection, structural biology, X-ray crystallography, Medicinal chemistry, 【초록키워드】 COVID-19, coronavirus disease, SARS-CoV-2, coronavirus, pandemic, antiviral drugs, 3CL pro, protease, antiviral activity, crystal structure, inhibitor, mechanism, 3CL, administration, Coronavirus replication, cysteine, acute respiratory syndrome, ligands, covalent binding, proteinase, derivative, derivatives, antiviral drug target, effective, caused, conserved, demonstrated, catalytic, modify, highlighting, pyrogallol, the SARS-CoV-2, 【제목키워드】 protease, inhibitor, 3CL, identification, pyrogallol, the SARS-CoV-2,