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Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently.The 3CL protease (3CLpro) is a highly conserved protease which is indispensable for CoVs replication,and is a promising target for development of broad-spectrum antiviral drugs.In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation,a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China.We showed that either the oral liquid of Shuanghuanglian,the lyophilized powder of Shuanghuanglian for injection or their bioactive components dose-dependently inhibited SARS-CoV-2 3CLpro as well as the replication of SARS-CoV-2 in Vero E6 cells.Baicalin and baicalein,two ingredients of Shuanghuanglian,were characterized as the first noncovalent,nonpeptidomimetic 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 was distinctly different from those of known 3CLpro inhibitors.Baicalein was productively 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 effectively prevent substrate access to the catalytic dyad within the active site.Overall,this study provides an example for exploring the in vitro potency of Chinese traditional patent medicines and effectively identifying bioactive ingredients toward a specific target,and gains evidence supporting the in vivo studies of Shuanghuanglian oral liquid as well as two natural products for COVID-19 treatment.