m persimmons to treat COVID-19.
This new review study by Taiwanese scientists focusses on the tannin family in fruits and the current knowledge about the activities of the compounds with regard to severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2.
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The anti-COVID-19 activities of tannins
The two major frontiers in battling the COVID-19 are infection and propagation of the SARS-CoV-2 coronaviruses, and the possible extreme reaction of the body’s immune system in response to pathogenic intrusion . While most research efforts have been devoted to preventing viral infection or eradicating the virus from the body, relatively less attention has been focused on developing methods to cope with the inflammatory responses, the “cytokine storm”, over the course of COVID-19.
Elevations of IL-6, IL-1β, TNF-α, IFN-γ and IL-10, as well as reductions in CD4+ and CD8+ T lymphocytes have been observed in COVID-19 patients, especially in severe cases . Currently, several polyphenol-based  and tannin-based clinical trials (NCT04911777 , NCT04403646 , and IRCT20200418047122N1 ) have been conducted with COVID-19 patients. Oral tannins extracted from quebracho and chestnut in combination with B12 vitamin and standard treatment reduced macrophage inflammatory protein-1α (MIP-1α) and TNF-α levels in hospitalized COVID-19 patients .
In a Syrian hamster model of COVID-19, persimmon-derived tannins pre-administered by oral gavage were able to suppress SARS-CoV-2 titers, reduce the severity of pneumonia and decrease inflammation-related gene expression such as IL-6, TNF-α, and IFN-γ .
The transmembrane protease serine 2 TMPRSS2 is an essential cell surface protease which processes the viral surface spike protein (S protein) to enhance its binding to the cell surface receptor ACE2 (angiotensin converting enzyme 2) followed by cell entry via membrane fusion.
The intracellular viral genomic RNA is then translated into polyproteins which are subject to further proteolytic cleavage by the viral main protease/3-chymotrypsin-like 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).