The enzyme whose function is blocked is the main protease in SARS-COV2. The virus requires this enzyme to replicate. If this main protease is blocked, the virus cannot survive.
Flavan-3-ols and proanthocyanidins (PAs) are two groups of plant flavonoids. They commonly exist in fruits, food products, and beverages, such as grape, strawberry, persimmon, cranberry, blueberry, cacao nuts, chocolate, green tea, and wines (Monagas et al., 2003). Common flavan-3-ol aglycones in these plant products include (–)-epicatechin (EC), (+)-catechin (CA), (–)-epigallocatechin (EGC), (+)-gallocatechin (GC), (–)-epiafzelechin (EAF), and (+)-afzelechin (AF) (Figure 2; Xie and Dixon, 2005). Common flavan-3-ol gallates include (–)-epicatechin-3-O-gallate (ECG), (+)-catechin-3-O-gallate (CAG), (–)-gallatechin-3-O-gallate (GCG), (–)-epigallocatechin-3-O-galloate (EGCG), which are highly abundant in green tea.(Dai X. et al., 2020; Wang P. et al., 2020)
Multiple compounds from these two groups, such as CA, EPC, EGC, EGCG, procyanidin B2, and procyanidin A2, have been shown to have antiviral function (de Bruyne et al., 1999; Iwasawa et al., 2009), antibacterial activity (Molan et al., 2001; Howell et al., 2005), anticancer (Ohata et al., 2005; Suganuma et al., 2011), anti-cardiovascular diseases (Loke et al., 2008; Panneerselvam et al., 2010; MacRae et al., 2019), and anti-aging diseases (Levites et al., 2003; Li et al., 2004; Weinreb et al., 2004). In particular, the anti-viral activity suggests that flavan-3-ols and PAs are appropriate targets for screening potential anti-SARS-Cov-2 medicines.
Both docking simulation and in vitro assays showed that the stereo configurations, galloylation, and oligomeric types of flavan-3-ols affected the ligand-protein binding features and inhibitory activity.
In summary, although these natural extracts have not been tested for the inhibitory efficacy in animals and humans, based on their inhibitory activity in vitro, we propose that an increased consumption of these common products can enhance preventing against SARS-Cov-2 and improving the COVID-19.
Conclusion, both docking simulation and in vitro assay showed that (–)-catechin-3-O-gallate (7), (–)-epicatechin-3-O-gallate (8), (–)-gallocatechin-3-O-gallate (9), and (–)-epigallocatechin-3-O-gallate (10), procyanidin B1 (11) and B2 (12) inhibited the Mpro activity of SARS-Cov-2. Moreover, these compound-rich extracts of green tea, muscadine grape, cacao, and dark chocolate also inhibited the Mpro activity. Given that there is not an effective medicine for the treatment of COVID-19 and not a vaccine for preventing against the SARS-Cov-2 infection and transmission, these data recommend that these nutraceutical compounds and extracts of green tea, grape, and cacao can be utilized to interfere the devastation of SARS-Cov-2.
Akagi, T., Ikegami, A., Suzuki, Y., Yoshida, J., Yamada, M., Sato, A., et al. (2009). Expression balances of structural genes in shikimate and flavonoid biosynthesis cause a difference in proanthocyanidin accumulation in persimmon (Diospyros kaki Thunb.) fruit. Planta 230, 899–915. doi: 10.1007/s00425-009-0991-6 PubMed Abstract | CrossRef Full Text | Google Scholar
Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., et al. (2020). A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N. Engl. J. Med. 382, 1787–1799. doi: 10.1056/NEJMc2008043 PubMed Abstract | CrossRef Full Text | Google Scholar
Chavarria-Miró, G., Anfruns-Estrada, E., Guix, S., Paraira, M., Galofré, B, Sáanchez, G., et al. (2020). Sentinel surveillance of SARS-CoV-2 in wastewater anticipates the occurrence of COVID-19 cases. medRxiv. [Preprint]. doi: 10.1101/2020.06.13.20129627 PubMed Abstract | CrossRef Full Text | Google Scholar
Chen, L., Gui, C., Luo, X., Yang, Q., Günther, S., Scandella, E., et al. (2005). Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro. J. Virol. 79, 7095–7103. doi: 10.1128/JVI.79.11.7095-7103.2005 PubMed Abstract | CrossRef Full Text | Google Scholar
Colson, P., Rolain, J.-M., and Raoult, D. (2020). Chloroquine for the 2019 novel coronavirus SARS-CoV-2. Int. J. Antimicrob. Agents 55, 105923–105923. doi: 10.1016/j.ijantimicag.2020.105923 CrossRef Full Text | Google Scholar
Dai, W., Zhang, B., Jiang, X.-M., Su, H., Li, J., Zhao, Y., et al. (2020). Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science 368, 1331–1335. doi: 10.1126/science.abb4489 PubMed Abstract | CrossRef Full Text | Google Scholar
Dai, X., Liu, Y., Zhuang, J., Yao, S., Liu, L., Jiang, X., et al. (2020). Discovery and characterization of tannase genes in plants: roles in hydrolysis of tannins. New Phytol. 226, 1104–1116. doi: 10.1111/nph.16425 PubMed Abstract | CrossRef Full Text | Google Scholar
de Bruyne, T., Pieters, L., Witvrouw, M., de Clercq, E., vanden Berghe, D., and Vlietinck, A. J. (1999). Biological evaluation of proanthocyanidin dimers and related polyphenols. J. Nat. Prod. 62, 954–958. doi: 10.1021/np980481o PubMed Abstract | CrossRef Full Text | Google Scholar
Fischer, T. C., Mirbeth, B., Rentsch, J., Sutter, C., Ring, L., Flachowsky, H., et al. (2014). Premature and ectopic anthocyanin formation by silencing of anthocyanidin reductase in strawberry (Fragaria x ananassa). New Phytol. 201, 440–451. doi: 10.1111/nph.12528 PubMed Abstract | CrossRef Full Text | Google Scholar
Foo, L. Y., Lu, Y., Howell, A. B., and Vorsa, N. (2000a). The structure of cranberry proanthocyanidins which inhibit adherence of uropathogenic P-fimbriated Escherichia coli in vitro. Phytochemistry 54, 173–181 doi: 10.1016/S0031-9422(99)00573-7 PubMed Abstract | CrossRef Full Text | Google Scholar
Foo, L. Y., Lu, Y., Howell, A. B., and Vorsa, N. (2000b). A-type proanthocyanidin trimers from cranberry that inhibit adherence of uropathogenic P-fimbriated Escherichia coli. J. Nat. Prod. 63, 1225–1228 doi: 10.1021/np000128u PubMed Abstract | CrossRef Full Text | Google Scholar
Fossen, T., Rayyan, S., and Andersen, O. M. (2004). Dimeric anthocyanins from strawberry (Fragaria ananassa) consisting of pelargonidin 3-glucoside covalently linked to four flavan-3-ols. Phytochemistry 65, 1421–1428. doi: 10.1016/j.phytochem.2004.05.003 PubMed Abstract | CrossRef Full Text | Google Scholar
Ghosh, R., Chakraborty, A., Biswas, A., and Chowdhuri, S. (2020). Evaluation of green tea polyphenols as novel corona virus (SARS CoV-2) main protease (Mpro) inhibitors - an in silico docking and molecular dynamics simulation study. J. Biomol. Struct. Dyn. 1–13. doi: 10.1080/07391102.2020.1779818 PubMed Abstract | CrossRef Full Text | Google Scholar
Gu, L., Kelm, M., Hammerstone, J. F., Beecher, G., Cunningham, D., AVAnnozzi, S., et al. (2002). Fractionation of polymeric procyanidins from lowbush blueberry and quantification of procyanidins in selected foods with an optimized normal-phase HPLC-MS fluorescent detection method. J. Agric. Food Chem. 50, 4852–4860 doi: 10.1021/jf020214v PubMed Abstract | CrossRef Full Text | Google Scholar
Helms, J., Kremer, S., Merdji, H., Clere-Jehl, R., Schenck, M., Kummerlen, C., et al. (2020). Neurologic features in severe SARS-CoV-2 infection. N. Engl. J. Med. 382, 2268–2270. doi: 10.1056/NEJMc2008597 CrossRef Full Text |