 cysteine protease (Mpro/3CLpro) to produce non-structural functional proteins essential for viral propagation (Figure 1) [65-70].
It has been demonstrated by multiple groups that tannic acid is a potent dual inhibitor of TMPRSS2 and Mpro/3CLpro to inhibit the SARS-CoV-2 activity [65-69].
Tannic acid inhibits Mpro/3CLpro with IC50 ranging from 1 μM to 13.4 Μm [65-69], and inhibits TMPRSS2 with IC50 ranging from 2.31 μM to 50 μM [68, 69]. The variable IC50 may result from the different methodologies such as fluorescence resonance energy transfer and ELISA-based enzymatic assays.
Importantly, the dual inhibition of TMPRSS2 and Mpro/3CLpro by tannic acid can be translated into suppression of cellular entry of the virus . Thus, tannic acid shows high potential for inhibition of SARS-CoV-2 among plant-derived polyphenols. Similar inhibitory activities of Mpro/3CLpro by the tannins of dimeric proanthocyanidins , punicalagin  and mixtures of tannic acid with plant-derived polyphenols  have also been observed in in vitro studies.
Consistently, it has been reported that green tea-derived tannins inhibited viral replication of SARS-CoV-2 in vitro and stably persist in the pharyngeal mucosa 1 hour after administration by throat spray , supporting the potential of green tea tannins in anti-COVID-19 therapies.
Moreover, the hydrolysable tannins such as pedunculagin, tercatain, and castalin have been demonstrated to be potential inhibitors of SARS-CoV-2 using the molecular operating environment software (MOE 09) which is an integrated computer-aided molecular design platform .
These natural compounds are predicted to be able to bind to the catalytic dyad residues of Mpro/3CLpro and inhibit the enzyme activity . It is worth mentioning that oral administration of highly-purified isomers of tannic acid exerts anti-COVID-19 activity against both the omicron and delta variants . A phase III clinical trial will be carried out in 2022 (NCT04911777).