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/lp/wolters-kluwer-health/tea-as-a-natural-gift-for-discovering-antiviral-candidates-FKVb1V00gK
- Publisher
- Wolters Kluwer Health
- Copyright
- Copyright © 2022 Tianjin University of Traditional Chinese Medicine.
- ISSN
- 2765-8619
- DOI
- 10.1097/hm9.0000000000000048
- Publisher site
- See Article on Publisher Site
Abstract
Coronavirus disease (COVID-19) remains rampant worldwide and poses a serious threat to human health. Tea is a medicinal and edible homologous plant that exhibits potential anti-SARS-CoV-2 properties via the prevention of virus entry into host cells, inhibition of virus replication, and enhancement of the innate and cellular immune responses. In this review, the properties of six major types of tea were systematically summarized, including green tea, yellow tea, white tea, oolong tea, black tea, and dark tea. We focused on the primary components of tea exhibiting antiviral activities, which included (–)-epigallocatechin-3-gallate, (–)-gallocatechin gallate, tannic acid, oolonghomobisflavan A, theaflavins, and white-tip silver needle flavonoids. Among them, (–)-epigallocatechin-3-gallate is proposed to be an antiviral compound that interferes with the entire life cycle of SARS-CoV-2 by balancing inflammation and immunity. Thus, this compound can serve as a promising lead structure for the development of SARS-CoV-2 inhibitors. Keywords: Catechins, (–)-Epigallocatechin-3-gallate, SARS-CoV-2, Tea Graphical abstract: http://links.lww.com/AHM/A39. [2] use in both treatment and prevention , yet the underly- Introduction ing mechanism of TCM action is difficult to fully eluci- As of August 12, 2022, over 585 million cases of the date. The correct symbol is “due to characteristics of its coronavirus disease 2019 (COVID-19) have been con- multi-components, multi-targets, and multi-pathways”. firmed, and more than 6.4 million deaths have been Therefore, it is imperative to screen bioactive substances reported by the World Health Organization. COVID-19 and investigate the underlying mechanisms of TCM [1] caused by SARS-CoV-2 continues to spread globally . based on modern scientific theories and technologies. Fortunately, therapeutics with traditional Chinese med- It will be helpful to elucidate the principle of TCM in icine (TCM) combined with Western medicine has been regard to battling COVID-19 infection and facilitate the demonstrated as a successful practice for the treatment spread of the use of TCM throughout the world. of COVID-19. TCM therapies such as “three TCM As a medicinal and edible homologous plant, tea makes drugs and three herbal formulas” (Xuebijing injections, a popular beverage that has been reported to inhibit SARS- Lianhua Qingwen capsules, Jinhua Qinggan granules, [3–5] CoV-2 activity . As a natural plant, tea is rich in various Qingfei Paidu formula, Huashi Baidu formula, and substances such as polyphenols, pigments, micronutrients, Xuanfei Baidu formula) exhibited remarkable efficacy amino acids, and vitamins. According to previous research, against COVID-19. TCM represents a powerful tool for the primary compounds that prevent viral infections in tea, which are (–)-epigallocatechin-3-gallate (EGCG), (–)-gal- locatechin gallate (GCG), tannic acid (TA), oolonghomo- Changjian Wang and Zhiying Yang contributed equally to this work. bisflavan A (OFA), theaflavins (TFs), and white-tip silver State Key Laboratory of Component-based Chinese Medicine, [3] needle flavonoids (WTSNF) . Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin In this review, the six major types of tea–green tea, yel- University of Traditional Chinese Medicine, Tianjin, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, China; Bioentropy low tea, white tea, oolong tea, black tea, and dark tea, Therapeutics Inc., Cambridge, MA, USA are systematically summarized. To identify attractive drug *Corresponding author. Weili Wang, Bioentropy Therapeutics Inc., 186 targets against SARS-CoV-2, potential active compounds Alewife Brook Pkwy, Cambridge, MA 02138, USA, E-mail: wlwang@ from tea were surveyed. This review will provide guidance post.harvard.edu; Min Zhang, State Key Laboratory of Component- for the discovery of novel anti-SARS-CoV-2 candidates. based Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China, E-mail: zhangm036@tjutcm.edu.cn. The types of tea plants Copyright © 2022 Tianjin University of Traditional Chinese Medicine. As a beverage, tea was prepared from the leaves of This is an open-access article distributed under the terms of the [6] Camellia sinensis in ancient China and initially used Creative Commons Attribution-Non Commercial-No Derivatives as a survival food. The medicinal functions of tea have License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be been gradually discovered and recognized as a result of changed in any way or used commercially without permission from the its widespread consumption. During the Tang Dynasty, journal. tea was honored as a cure for all diseases, thus provid- Acupuncture and Herbal Medicine (2022) 2:4 ing a great summary of its medical benefits. Furthermore, Received 16 August 2022 / Accepted 29 September 2022 tea has been demonstrated to possess numerous phar- macological effects such as anti-oxidation, anti-aging, http://dx.doi.org/10.1097/HM9.0000000000000048 211 Wang et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com [12] anti-cancer, immune regulation, metabolism regulation, preparation process . Catechins are the primary com- and physiological regulation, particularly in regard to ponents in tea polyphenols. These compounds account [7] antiviral and anti-inflammatory regulatory functions . for 70%–80% of catechins, including catechin (C), epi- In China, tea plants can be classified according to a catechin (EC), epigallocatechin (EGC), epicatechin gal- [13] number of parameters such as quality, production area, late (ECG), and EGCG . Among these, EGCG accounts [14] cultivation environment, and processing method. As for 50%−80% of the total catechin content . The presented in Figure 1, tea can be divided into six major ingredients mentioned above contribute to the antiviral types according to the extent of fermentation, and these activity of green tea. types include green tea (non-fermented), yellow tea (fer- mentation degree of 10%−20%), white tea (fermenta- Yellow tea tion degree of 10%−20%), oolong tea (fermentation degree of 30%−60%), black tea (fermentation degree Yellow tea is a slightly fermented tea with a fermenta- tion degree of 10%−20% and is referred to as yellow of 80%−90%), and dark tea (fermentation degree of [8] 100%) . The fermentation process is primarily deter- tea based on the color of the leaves changing from green to yellow during fermentation. It yields a bright yellow mined due to the oxidative polymerization and conden- sation of catechins that are catalyzed by endogenous tea liquid with a fresh and mellow taste. This tea can be divided into three types: yellow bud tea, yellow small polyphenol oxidase and peroxidase. tea, and yellow big tea. The renowned yellow teas are Jun Shan Silver Needle, Huo Shan Yellow Bud, Big Leaf Green tea Light Tea, and Huo Shan Huang Da Tea. Green tea is the only type of tea that is not oxidized and Yellow tea contains catechins, flavonoids, alkaloids, [15] named according to its yellow-green liquor and unfer- amino acids, and other ingredients . The initial process mented green leaves. It possesses a light aroma and tastes is the same as that of green tea regarding to roasting or slightly bitter. This tea accounts for approximately 20% steaming, and it then requires a unique step known as [9] of the total tea production worldwide . The famous “sealed yellowing” that can remove the grassy flavor of [16] green teas in China are Xihu Longjing Tea, Lu Shan green tea while still retaining the healthcare values . Mist Tea, Bi Luo Chun Tea, and Huang Shan Mao Feng Prolonged yellowing has been reported to increase the Tea. Fresh tea leaves are roasted or steamed to destroy contents of amino acids, soluble sugar, TFs, and non-es- the enzymes responsible for decomposing the pigments terified catechins while decreasing the contents of poly- in leaves, thus maintaining maintain their green color phenols, flavonols, thearubigins, caffeine, and esterified [8,10] [17] during the rolling and drying process . Green tea con- catechins . In particular, the ester catechin content in tains high levels of natural polyphenols. yellow tea was significantly lower than that in green The major compounds in green tea are catechins, phe- tea, and the content of non-esterified catechins and [11] nolic acids, flavonoids, and amino acids . Among these, amino acids was higher than that in green tea. The total catechins in green tea exhibit higher anti-oxidant activ- amount of tea polyphenols is similar to that of green tea [18] ity due to the minimal oxidation that occurs during the and accounts for 20.44%–27.66% of the dry weight . Figure 1. Six types of tea and their primary chemical compositions. 212 Wang et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com After fermentation, 85% of natural substances are Black Tea, and Lapsang Souchong Tea are famous in retained, and these substances have been demonstrated China. The liquid is clear and bright with a red-orange to possess anti-cancer, anti-bacterial, free radical scav- or bright red color, and a mellow, fresh and sweet taste. [19] enging , gastrointestinal protection, and anti-oxidant Black tea contains not only catechins and TFs but also [20] [12] activity . phenolic acids, flavonols, and amino acids . Four pro- cessing steps include withering, rolling, fermentation, and drying. The activity of enzymes is increased with White tea deepened fermentation that is used to degrade chloro- White tea is a type of micro-fermented tea that originates phyll, drive the polymerization of catechins and polyphe- from Fujian Province (China) and made from buds and nols, and generate colored substances such as TFs and new leaves with minimal processing steps such as wither- thearubigins. Thus, black tea possesses a bright orange- [21] ing and drying . On the leaf surface, there is a covering red color. Four major TFs have been identified, including of white fuzz that is referred to as light frost that can pro- TF, theaflavin-3-gallate (TF-3-G), theaflavin-3’-gallate [28] tect the growth of new leaves from insects. Additionally, (TF-3ʹ-G), and theaflavin-3,3’-digallate (TF-3,3ʹ-diG) . the tea broth appears light in color and therefore it is Catechins can be oxidized and polymerized into high- referred to as white tea. Bai Hao Silver Needle and Bai er-molecular-weight polyphenols by endogenous poly- [29] Mu Dan Tea are the most famous white teas. phenol oxidase and peroxidase which have been [30] White tea has been deemed to be an excellent anti-in- reported to exhibit antiviral activities . flammatory folk herb that exhibits better activities with the extension of storage time. Modern research has Dark tea demonstrated that it is rich in polyphenols and flavonoids Dark tea is a unique type of fermented tea that is pro- that contribute to its anti-oxidant and anti-inflammatory duced through solid-state fermentation by microorgan- activities. After withering for a long period of time, the [31] isms and possesses oily black or dark brown leaves due catechin content was markedly reduced due to chemi- to its long accumulation time and fermentation. Famous cal reactions that included oxidative polymerization and dark teas in China are An Hua Dark Tea, Pu’er Tea, Liu other reactions. However, the contents of TF, thearub- Pao Dark Tea, and Ya An Tibetan Tea. The basic pro- igin, tea pigments, gallic acids, and acyl procyanidins duction process consists of four steps that include fixing, increased significantly. In white tea, the total amount of rolling, stacking, and drying. Stacking is believed to be a amino acids is 1.13 to 2.25 fold higher than that of other [22] key step in the production of high-quality dark tea. This teas , and the content of free amino acids is the high- [23] tea is abundant in various compounds, including cate- est and ranges from 5.97% to 8.89% . A large number chin derivatives, flavonols, flavonoids, glycosides, phe- of animal and cell experiments have revealed that white [32–34] nolic acids, alkaloids, and terpenoids . Meanwhile, tea exerts various beneficial activities such as anti-in- it has received much attention due to its excellent health flammatory, anti-oxidant, anti-tumor, bacterial and viral benefits such as prevention of hypertension and cardio- inhibition activities, and protection of the cardiovascular [24] vascular disease, relief of metabolic syndrome, and regu- system and liver . [35] lation of intestinal function and weight loss . Oolong tea Structure of SARS-CoV-2 and the attractive drug Oolong tea is also referred to as Wu Long Tea in Chinese targets and considered as a semi-fermented tea originating from [25] Coronaviruses are enveloped, single-stranded, positive- Fujian Province (China) that possesses a strong aroma sense RNA viruses belonging to the Orthocoronavirinae and light sweetness. Its leaves are green in the middle subfamily of Coronaviridae. They can be divided into and red at the edge, and thus its leaves are typically four major genera according to their genome sequences referred to as red-edged green tea leaves. The manufac- and serological reactions, including Alphacoronavirus, turing process consists of four steps that include wither- Betacoronavirus, Gammacoronavirus, and Deltacoro ing, kneading, fermenting, and baking. It combines the [36–37] navirus . SARS-CoV-2 belongs to the subfamily processing methods of both green tea and black tea, thus Betacoronavirus that possesses a unique structural fea- resulting in a mixed taste. In China, Da Hong Pao Tea ture on the virion surface referred to as a crown that and An Xi Tie Guan Yin Tea possess a global reputation. contributes to the diversity of subunits. SARS-CoV-2 With the extension of fermentation time, the sweet and encodes 14 open reading frames (ORFs). Each of these green fruity flavors are enhanced, while the bitter flavor ORFs (with except ORF10) was translated into 29 does not change. Furthermore, the content of catechins [26] viral proteins. At the 3ʹ terminus of the viral genome, decreases, whereas that of TF increases significantly . they encode four structural proteins that include the Oolong tea also contains a number of active components spike (S), envelope (E), membrane (M), and nucleocap- such as alkaloids, polyphenols, flavonoids, amino acids, sid (N) proteins. At the 5ʹ terminus, two-thirds of the proteins, polysaccharides, and vitamins that are benefi- [27] genome encodes two overlapping polyproteins (pp1a cial to human health . and pp1ab) that are digested by viral proteases into 16 non-structural proteins (Nsps) that play an essential Black tea [38] role in viral replication and transcription . Sixteen Black tea is a fully fermented tea and the most popu- Nsps are necessary for the forming of the viral repli- [14] lar tea worldwide . Qi Men Black Tea, Yun Nan Dian cation transcription complex (RTC) for viral RNA 213 Wang et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com [39] synthesis in host cells . Unlike other Nsps, Nsp5 GCG, and WTSNF can regulate a variety of cellular pro (main protease, M ) and Nsp3 (papain-like protease, inflammatory and immune factors, including interleukin pro PL ), two highly conserved proteases, are produced by (IL)-6, IL-1β, IL-17, IL-8, tumor necrosis factor-α (TNF- autolytic cleavage. They then cleave pp1a and pp1ab to α), and interferon-γ (IFN-γ), thus resulting in diminished [40] produce other Nsps and form mature viral genomes . and restored inflammation caused by SARS-CoV-2 inva- Nsp12 (RNA-dependent RNA polymerase, RdRp) sion of host cells. pro that is generated by M cleavage is another import- ant Nsp required for new virion assembly, and it has Catechins [41] been demonstrated to be the target of remdesivir . pro pro Therefore, M , PL , and RdRp are thought to be the Catechins is a class of phenolic active substances extracted from natural plants that account for approximately 70% primary targets for the development of SARS-CoV-2 [70] [42] inhibitors . During the SARS-CoV-2 life cycle, viruses of the total tea polyphenols , and it has been reported to exhibit beneficial effects in vitro and in vivo such as enter host cells through S protein binding to angioten- sin-converting enzyme 2 (ACE2) receptors on the cell anti-oxidant and anti-bacterial activity, obesity control, and free radical scavenging. Catechins in tea include EC, surface. This step relies on the action of transmembrane [71] protease serine (TMPRSS2) that mediates the cleavage GC, EGC, CG, ECG, GCG, and EGCG which exhibit antiviral functions and protect against diseases caused of the S protein and initiates the membrane fusion of [43] viruses with the host . Therefore, intervention in the by oxidative stress and inflammation. Compounds with antiviral activity in tea may contribute to curbing the binding of S protein to ACE2 receptor represents an ideal and promising approach. Thus, TMPRSS2 is a devastation resulting from COVID-19 infection caused [72] by SARS-CoV-2 . potential antiviral target. An increasing number of studies have demonstrated that the release of virions into the body through exo- EGCG cytosis, which can trigger a cytokine storm, ultimately EGCG is a major compound derived from green tea leading to systemic inflammation and damage to tissue with a basic flavan-3-ol structure that has been reported and organ. Hence, an integrated treatment approach was to exert numerous pharmacological effects, including proposed that targets not only the pathogen but also the [73] [74] anti-tumor , anti-oxidation , degenerative disease key pathways of inflammation and immune response [75] [76] [77] protection , anti-bacterial , antiviral , hypogly- such as the NF-κB and JAK-STAT pathways. [78] [79] cemic , anti-mutagenic , anti-inflammatory, and [80–81] immunomodulatory properties . EGCG is likely Anti-SARS-CoV-2 compounds in tea to represent a satisfactory candidate based on the Multiple compounds possess antiviral activity in tea, demonstrated evidence of inhibition of SARS-CoV-2 [3] including EGCG, GCG, TA, OFA, TFs, and WTSNF entry and virus infection in vitro . Furthermore, that can not only inhibit the invasion and replication of EGCG has been identified as a potential inhibitor of pro pro[48,82] SARS-CoV-2 to some extent but can also regulate and M and PL . restore the inflammatory response. They play a key role in the fight against SARS-CoV-2 infection. As presented Inhibition of SARS-CoV-2 entry into host cells by EGCG in Table 1, EGCG can activate Nrf2 which inhibits the expression of ACE2 receptors to reduce the levels of During infection, the S protein that is embedded in the ACE2 receptors. TA acts on TMPRSS2 to prevent SARS- SARS-CoV-2 surface lipid envelope recognizes ACE2 CoV-2 from entering host cells. Moreover, EGCG, GCG, receptors and binds to them to allow for uncoating. In TA, OFA, and TFs have been demonstrated to interfere this step, the S protein is cleaved by certain proteases with the replication of SARS-CoV-2 via the differential (TMPRSS2 and furin) to promote membrane fusion. pro pro targeting of M , PL , or RdRp. Additionally, EGCG, Then, the viral genomes are injected into host cells to Table 1 Major antiviral compounds in tea and their targets and functions Compounds Targets Primary functions References [44–47] EGCG Nrf2 Reduction of ACE2 receptor expression in airway epithelial cells by activating Nrf2 pro pro pro pro [48–54] M /PL /RdRp Interference with SARS-CoV-2 replication by inhibition of M , PL , and RdRp [55–63] Nrf2/NF-κB pathway/JAK-STAT pathway Reduction of the levels of IL-6, IL-1β, IL-17, IL-8, TNF-α, IFN-γ, and other pro-inflammatory factors [64] GCG N protein Interference with SARS-CoV-2 replication by disrupting the LLPS of N protein pro pro [49] M Interference with SARS-CoV-2 replication by inhibition of M [65] Reduction of the levels of IL-1α, TNF-α, IL-4, and IL-1 pro pro [66] TA M Interference with SARS-CoV-2 replication by inhibiting M [66] TMPRSS2 Interference with SARS-CoV-2 invasion by inhibiting TMPRSS2 pro pro [6] OFA M Interference with SARS-CoV-2 replication by inhibition of M pro pro pro pro [5,67–68] TFs M /PL /RdRp Interference with M , PL , and RdRp to block SARS-CoV-2 replication [69] WTSNF NF-κB pathway Reduction in the levels of IL-6, IL-1β, IL-17, IL-8, TNF-α, and IFN-γ EGCG: (–)-epigallocatechin-3-gallate; GCG: (–)-gallocatechin gallate; LLPS: Liquid–liquid phase separation; OFA: Oolonghomobisflavan A; TA: Tannic acid; TFs: theaflavins; WTSNF: white-tip silver needle flavonoids. 214 Wang et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com Interference with the replication of SARS-CoV-2 by EGCG translate polyproteins that are cleaved by the primary pro pro proteases (M and PL ) to produce mature Nsps. This Regarding the replication of SARS-CoV-2, studies have pro pro[30,48,84] is a key step in the replication of SARS-CoV-2. These demonstrated that EGCG inhibits M and PL . Nsps are assembled to form the RTC for the transcription pro The IC value of EGCG for M was reported at 73 and synthesis of new genomic RNAs. All viral proteins μmol/L, and molecular docking was used to reveal the are translated and assembled into mature virus particles [49–53] possible binding mechanism . Research has also by the host translation machinery. Finally, mature viral revealed that EGCG plays a superior role in the inhi- particles are released by exocytosis and trigger a cascade pro [48,54] bition of PL by molecular docking . Furthermore, of immune responses. Cytokine storm is a lethal immune EGCG decreases the levels of viral RNA and proteins in response. infected cells to inhibit viral replication in vitro, and this pro pro[85–87] As presented in Figure 2, EGCG can interfere with is related to the inhibition of M and PL . SARS-CoV-2 entry into host cells by activating Nrf2 which can then downregulate ACE2 and TMPRSS2 Balance the inflammation and immunity by EGCG [44] expression . Nrf2 is reported to be an important cyto- protective transcription factor that regulates the expres- In the serum of patients with severe or critical COVID- [55] sion of various genes, including aging, anti-oxidation, 19 , cytokines such as IL-6, IL-1β, IL-17, IL-8, TNF-α, [56–57] detoxification, inflammation, neurodegeneration, immu- and IFN-γ are excessively elevated , ultimately lead- [45–47] nity, and antiviral response genes . ing to cytokine storm. EGCG can alleviate and restore Several studies have revealed that EGCG can interfere inflammation by regulating inflammatory pathways with the invasion of SARS-CoV-2. EGCG can inhibit the such as the NF-κB and JAK-STAT pathways to regu- multiplication of SARS-CoV-2 in pseudotyped models late the synthesis and secretion of several cytokines and [58–59] that have been employed to reveal the inhibitory activ- chemokines . Nrf2 also regulates inflammation by [3] ity of EGCG . Ohishi et al. revealed that EGCG could repressing pro-inflammatory factors and managing stress effectively interfere with the interaction between the and inflammatory responses. Studies have demonstrated [83] SARS-CoV-2 S protein RBD and ACE2 . that Nrf2 can counteract the NF-κB pathway that drives Figure 2. Potential inhibition of the SARS-CoV-2 life cycle and cytokine storm by EGCG treatment. 215 Wang et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com inflammatory responses in much experimental mod- that serves as a powerful target for the development of [60] [89] els . Nrf2 is considered to be an upstream regulator of effective antibodies for neutralization . Other stud- [61–62] cytokine production , and it not only regulates cel- ies have observed that GCG can effectively inhibit the lular defenses against oxidative stress but also induces expression of inflammatory factors such as IL-1α, TNF- [61,63] anti-inflammatory effects by its activation . Previous α, IL-4, and IL-1, and it is expected to provide a strong [65] studies have demonstrated that EGCG can activate Nrf2. defense against COVID-19 . Therefore, EGCG is a promising candidate for the rever- sal of excessive inflammation. Tannins Tannin is a category of water-soluble polyphenolic com- Molecular docking of EGCG with the primary targets of pounds that are primarily divided into two types that SARS-CoV-2 [90] include hydrolyzable tannins and condensed tannins . Tannins exhibit various biological activities, including According to previous studies, EGCG is a potential [91] [92] [93] anti-oxidant , anti-tumor , antiviral , and anti-bac- inhibitor of SARS-CoV-2. In this review, we used EGCG pro pro [94] terial activities. TA is a water-soluble polyphenol that as an example to dock with M (PDB ID:6LU7), PL is a member of the hydrolyzable tannins and is primar- (PDB ID:7JCM), and the S protein RBD-ACE2 (PDB [95] ily present in teas and fruits . In recent studies, TA has ID:7T9L) to predict the possible mechanisms. As pre- pro pro been demonstrated to inhibit both TMPRSS2 and M sented in Table 2, the docking score with M was [66,96] to prevent SARS-CoV-2 invasion and replication . TA ˗60.04 kcal/mol. As indicated in Figure 3A, the EGCG- pro also disrupts the interaction between the S protein RBD M complex exhibited van der Waals interactions, [97] and ACE2 receptors . Overall, TA may represent a use- hydrogen bonding, and other hydrophobic effects. ful strategy for preventing SARS-CoV-2 infections. TA EGCG formed two hydrogen bonds with the key amino is a natural product extracted from plants that possess acid residue Glu 166 and formed non-covalent interac- a good safety profile, is suitable for clinical trials, and tions such as pi-sulfur or pi-alkyl interactions with Cys exhibits good medicinal properties. 145 and His 41 that are important catalytic dyads in pro the active pocket of M domains I and II. The dock- pro ing score with PL was −54.12 kcal/mol. As presented OFA in Figure 3B, EGCG combined with the active pocket OFA is a typical compound in oolong tea and is a dimer (Cys 111, His 272 and Asp 286) and formed hydrogen [98] formed by EGCG . In silico docking and molecular bonds with Gly 266 and Tyr 268. The docking score for dynamics simulation studies revealed that OFA was EGCG for the S protein RBD-ACE2 was ˗55.15 kcal/ screened from a series of structurally similar com- mol. As presented in Figure 3C, EGCG combined with pounds in tea due to its excellent binding interaction the core region (Cys 378–Cys 432) and formed multiple pro with M . The virus suppressive effect was not signifi- hydrogen bonds with Tyr 385, Gly 395, Glu 398, and cantly different between OFA and other reported drugs Glu 402. It exhibited considerable binding affinity to (atazanavir, darunavir, and lopinavir) against COVID- block the interaction in the invasion and replication of [14] [51] 19 . OFA is a potentially active molecule that acts as SARS-CoV-2 . pro an inhibitor of M . GCG Tea pigments GCG is a type of catechin and is considered to be another Tea pigments are water-soluble phenolic pigment active compound in tea that acts against SARS-CoV-2, products derived from the oxidative polymerization and this compound can inhibit the replication of SARS- pro of tea polyphenols. During fermentation, a variety CoV-2 as a potential inhibitor of M . In silico docking of tea pigments are generated, including TFs, thearu- and molecular dynamics simulation studies revealed that bigins, and theabrownins. The higher the degree of GCG exhibited good binding and strong interactions pro fermentation, the greater the production of pig- with the key amino acid residues of M via hydropho- [99–100] [49,53] ment compounds . Studies have confirmed that bic or hydrogen bonding interactions . tea pigments exert various pharmacological effects. Additionally, GCG inhibits the replication of SARS- TFs exhibit anti-oxidant, anti-inflammatory, anti- CoV-2 by disturbing liquid–liquid phase separation [88] viral, anti-cancer, and neuroprotective properties. (LLPS) . LLPS is thought to be critical for N protein [64] Thearubigin possesses anti-inflammatory, bacterio- transcription and translation during viral assembly . static, and anti-oxidant properties. Theabrownin The N protein is a highly conserved RNA-binding factor exhibits lipid-lowering, weight loss, hypoglycemic, [101–103] and anti-tumor activities . Table 2 TFs are the products of the oxidative polymeriza- The docking scores of EGCG with the potential targets tion of catechins and the major components of tea [104] pigments , which are composed of four isomers CDOCKER INTERACTION ENERGY (kcal/mol) that include TF, theaflavin-3-gallate (TF2a), theafla- pro pro M PL S protein vin-3’-gallate (TF2b), and theaflavin-3,3’-digallate Compound (PDB:6LU7) (PDB: 7JCM) (PDB: 7T9L) [71,105] (TF3) . TFs have exhibited good antiviral activity `EGCG −60.04 −54.12 −55.15 against SARS-CoV-2 as reported by previous pharma- [30,106] EGCG: (–)-epigallocatechin-3-gallate. cological studies . 216 Wang et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com pro pro Figure 3. Molecular docking of EGCG with M (PDB: 6LU7) (A), PL (PDB: 7JCM) (B), and S protein (PDB: 7T9L) (C). Recent studies have determined that TFs can signifi- exhibit the highest binding affinities towards RdRp, pro pro [5] cantly inactivate SARS-CoV-2 in vitro. For example, M , and PL targets on SARS-CoV-2 . Jang et al. theasinensin A (TSA) and theafflavin 3,3’-di-O-gallate designed experiments to demonstrate that TF inhibits the pro (TFDG) can significantly reduce the infectiousness of activity of SARS-CoV-2 M in vitro in a dose-depen- [108] viruses, RNA replication of viruses in cells, and second- dent manner . Based on the studies illustrated above, ary virus production at a certain concentration. TSA and we conclude that TFs and their derivatives can diminish TFDG can prevent the interaction between the S protein the activity of SARS-CoV-2, thus displaying a potential [67] RBD and ACE2 receptors . Bioinformatics and molecu- and promising role in the fight against the COVID-19 lar docking studies by Maiti and Banerjee demonstrated outbreak. that the TF gallate exhibits greater binding affinity to the SARS-CoV-2 S protein than does hydroxychloroquine Flavonoids (HCQ), thus indicating its superior inhibitory activity [107] Flavonoid is a class of natural polyphenols that are dis- compared to that of HCQ . Theaflavin-3’-O-gallate (TFMG) is an enriched compound in black tea that has tributed widely in nature with extensive pharmacological activities, and it primarily exhibits anti-cardiovascular been demonstrated to block the active portion of SARS- CoV-2 RdRp with better docking than that of remde- disease, anti-oxidant, anti-cancer, anti-bacterial, anti-in- [109] [68] flammatory, and other related activities . WTSNF is sivir . Additionally, a virtual screening and molecular dynamics simulation study revealed that TF3 and TF2a a flavonoid that is unique to white tea and has been 217 Wang et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com [2] Huang K, Zhang P, Zhang Z, et al. Traditional Chinese medicine demonstrated to possess anti-oxidant and anti-inflam- (TCM) in the treatment of COVID-19 and other viral infections: matory properties that can ameliorate organ damage, efficacies and mechanisms. Pharmacol Ther 2021;225:107843. modulate the levels of relevant immune factors, inhibit [3] Henss L, Auste A, Schürmann C, et al. The green tea catechin epi- the expression of NF-κB, and reduce the levels of inflam- gallocatechin gallate inhibits SARS-CoV-2 infection. J Gen Virol 2021;102(4):001574. matory factors such as IL-6, IL-1β, IL-17, IL-8, TNF-α [4] Liu J, Bodnar BH, Meng F, et al. Epigallocatechin gallate from [69] and IFN-γ . 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Published: Dec 26, 2022