Tannic acid suppresses SARS-CoV-2 as a dual inhibitor of the viral main protease and the cellular TMPRSS2 protease

The cell surface protein TMPRSS2 (transmembrane protease serine 2) is an androgen-responsive serine protease important for prostate cancer progression and therefore an attractive therapeutic target. Besides its role in tumor biology, TMPRSS2 is also a key player in cellular entry by the SARS-CoV viruses. The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has resulted in huge losses in socio-economy, culture, and human lives for which safe and effective cures are highly demanded. The main protease (Mpro/3CLpro) of SARS-CoV-2 is a critical enzyme for viral propagation in host cells and, like TMPRSS2, has been exploited for treatment of the infectious disease. Numerous natural compounds abundant in common fruits have been suggested with anti-coronavirus infection in the previous outbreaks of SARS-CoV. Here we show that screening of these compounds identified tannic acid a potent inhibitor of both SARS-CoV-2 Mpro and TMPRSS2. Molecular analysis demonstrated that tannic acid formed a thermodynamically stable complex with the two proteins at a KD of 1.1 mM for Mpro and 1.77 mM for TMPRSS2. Tannic acid inhibited the activities of the two proteases with an IC50 of 13.4 mM for Mpro and 2.31 mM for TMPRSS2. Mpro protein. Consistently, functional assays using the virus particles pseudotyped (Vpp) of SARS-CoV2-S demonstrated that tannic acid suppressed viral entry into cells. Thus, our results demonstrate that tannic acid has high potential of developing anti-COVID-19 therapeutics as a potent dual inhibitor of two independent enzymes essential for SARS-CoV-2 infection.