key: cord-0845565-wopn2bvd authors: Bimonte, Sabrina; Forte, Cira Antonietta; Cuomo, Massimiliano; Esposito, Gennaro; Cascella, Marco; Cuomo, Arturo title: An Overview on the Potential Roles of EGCG in the Treatment of COVID-19 Infection date: 2021-10-28 journal: Drug Des Devel Ther DOI: 10.2147/dddt.s314666 sha: 12cf374ca64247d0888176382cd05b86f0240d38 doc_id: 845565 cord_uid: wopn2bvd Coronavirus disease-19 (COVID-19) pandemic is currently ongoing worldwide and causes a lot of deaths in many countries. Although different vaccines for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have been developed and are now available, there are no effective antiviral drugs to treat the disease, except for Remdesivir authorized by the US FDA to counteract the emergency. Thus, it can be useful to find alternative therapies based on the employment of natural compounds, with antiviral features, to circumvent SARS-CoV-2 infection. Pre-clinical studies highlighted the antiviral activities of epigallocatechin-3-gallate (EGCG), a catechin primarily found in green tea, against various viruses, including SARS-CoV-2. In this review, we summarize this experimental evidence and highlight the potential use of EGCG as an alternative therapeutic choice for the treatment of SARS-CoV-2 infection. SARS-Cov-2 is a novel coronavirus causing the severe acute respiratory syndrome spreading around the world since the end of 2019. 1,2 It belongs to a family of singlestranded RNA viruses (+ssRNA), as the severe acute respiratory syndrome virus (SARS-CoV) and the Middle East respiratory syndrome virus (MERS-CoV). SARS-CoV-2 infection can cause mild to severe pneumonia and its mortality rate is higher in patients with comorbidities and older patients. 3, 4 Although different vaccines for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have been developed and are now available, 5 there are no effective antiviral drugs to treat the disease, except for Remdesivir authorized by the United States Food and Drug Administration (US FDA) to counteract the emergency. 6 mRNA-based vaccines were developed by Moderna and Pfizer/BioNTech, 7, 8 but there is still uncertainty about their efficacy (~95%), safety, and immunogenicity concerning SARS-CoV-2 spike glycoprotein (S protein). Similarly, viral vector vaccines were produced by Johnson and Johnson and by the University of Oxford/AstraZeneca, although the safety of AstraZeneca's vaccine is currently under revision. 9, 10 Unfortunately, new strains of the virus have developed so far with new mutations and this could inhibit the effectiveness of vaccines, and delays the end of the pandemic. 11 Given the high infectivity of new mutations in the virus and the slowness of vaccine programming, herd immunity will be difficult to achieve in a short time. It is very likely that new coronavirus diseases may still emerge in the future. Thus, it can be necessary to develop alternative therapies based on the use of natural compounds, as epigallocatechin-3-gallate (EGCG), with antiviral features, to circumvent SARS-CoV-2 infection. EGCG, is the principal constituent and most important polyphenolic catechin found in green tea. [12] [13] [14] [15] [16] [17] [18] As largely reported, EGCG possesses many biological properties (ie antioxidant, antitumor, anti-inflammatory) due to a galloyl side chain contained in its chemical structure. 19 It has been shown that polyphenols and EGCG, through sticking with some molecules present in viruses, are able to regulate their functions. Specifically, EGCG by binding to the receptors present on the membrane of the host cells or directly to the viral surface inhibits the interaction between the host cells and the virus. As a result, EGCG represses the replication and the transcription of the virus, thus inactivating its activity. 20, 21 As recently detailed described by Wang et al, 22 EGCG has inhibitory activities towards different viruses. Specifically, EGCG is able to suppress the replication, the transcription and the infection of DNA virus as Hepatitis B Virus (HBV), [23] [24] [25] [26] [27] Herpes Simplex Virus (HSV) [28] [29] [30] [31] and Epstein-Barr Virus (EBV) through different molecular mechanisms. [32] [33] [34] [35] Moreover, EGCG has similar effects on RNA virus as Human Immunodeficiency Virus (HIV), [37] [38] [39] [40] [41] [42] Hepatitis C virus (HCV), [43] [44] [45] and Influenza A virus (IAV). [46] [47] [48] Additionally, in vitro studies demonstrated that EGCG is capable to inhibit the replication of some Enterovirus (CVB3, EV71) by regulating the oxidative stress of host cells. 49, 50 Similar effects were also detected in Arboviruses, particularly in Chikungunya virus (CHIKV). [51] [52] [53] [54] [55] Finally, several pre-clinical studies confirmed the antiviral activity of EGCG also against Coronaviruses, especially against SARS-Cov-2. [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] Basically, EGCG can inhibit the cell entry of these viruses or their replication and transcription, through different molecular mechanisms which are not completely known. In this review, we summarize these experimental pieces of evidence and highlighted the potential use of EGCG as an alternative therapeutic choice for alleviating or treat SARS-Cov-2 infection. COVID-19 is caused by SARS-CoV-2 infection. 56 The initial clinical manifestations of COVID-19 include respiratory symptoms, such as fever, fatigue and dry cough, are accompanied by atypical clinical manifestations such as sore throat, headache and diarrhea. 57 Around one week later, patients exhibited difficulty breathing and hypoxia, during which the secretion of intracellular pro-inflammatory factors Interleukin-6 (IL-6), Interleukin-17 (IL-17) and tumor necrosis factor α (TNF-α)) increased significantly, and the total number of circulating lymphocytes decreased. Then, the symptoms rapidly deteriorated into acute respiratory distress syndrome (ARDS), sepsis, blood coagulation dysfunction and irreversible metabolic acidosis. Eventually, some severe cases would lead to death. Structurally, SARS-CoV-2 contains four proteins including spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. During host cell entry, SARS-CoV -2 relies on its S proteins for binding to the host cell-surface receptor. The S protein binds to the host receptor through the receptor-binding domain (RBD) in the S1 subunit, followed by the fusion of the S2 subunit to the cell membrane. SARS-CoV-2 recognizes the cell membrane receptor angiotensinconverting enzyme 2 (ACE2) receptor to bind with the viral S protein, thus forming RBD-ACE2 complex, by which the virus is embedded into the host cell where it starts replication. Thus, if a substance can bind the S protein, or possesses a strong affinity to ACE2 receptor, which blocks the formation of RBD-ACE2 complex, it could suppress the viral entry into host cells. Regarding the antiviral effects of EGCG on SARS-CoV-2, different pre-clinical studies have been performed (Table 1) . Basically, the inhibition effects of EGCG on SARS-CoV-2 replication occur through its actions on the ACE2 receptor, the main protease (Mpro, a 3C-like protease) and RNA-dependent RNA polymerase (RdRp) ( Figure 1 ). Mhatre et al 58 reviewed the antiviral activities of EGCG theaflavin-3,3′-digallate (TF3) against positive-sense single-stranded RNA viruses, including SARS-CoV-2. The authors suggested that both the tea polyphenols are capable to interact with the receptors present in the structure of SARS-CoV-2 virus, thus inhibiting its replication. Particularly, the theaflavins (TFs), can be employed as prophylactic agents due to their capacity to bind Spike receptor-binding domain (RBD), the principal binding domain of the S protein located on the S1 subunit of SARS-CoV-2 virus. EGCG can be used as a potential prophylactic due to its ability to dock to various active sites of SARS-CoV-2 virus. The authors highlighted the needing of additional studies on the specificity, safety, and efficacy of these polyphenols, to confirm their use not only as a dietary supplement, but also as therapeutic agents for COVID-19 infections. Menegazzi et al, 59 speculated that EGCG and others catechins (ie, GTE) supplementation could be effective in controlling the inflammation damages occurring in SARS-CoV-2 infection, through complex molecular mechanisms involving different interacting transcriptor factors (ie signal transducer and activator of transcription, STAT; nuclear factor kappa-light-chain-enhancer of activated B cells, NF-κB; NF-E2-related factor 2; Nuclear Factor Erythroid-Derived 2-Related Factor 2, Nrf2). Similarly, Mendonca et al, 60 suggested that the combination (Continued) Here, we summarized recent findings on the potential role of EGCG in the treatment of SARS-CoV-2 infection. Accumulated pieces of evidence reported that EGCG has antiviral properties against different viruses, including SARS-Cov-2. 22 Specifically, it has been proved that EGCG inhibits the enzymatic activity of the coronavirus 3CL protease, thus interfering with its replication. Moreover, EGCG can regulate specific target as the viral S protein and RdRp. EGCG is also capable of inhibiting the replication of coronaviruses in cell cultures. Results from molecular docking analyses demonstrated that EGCG prevents SARS-CoV-2 entry into the target cell through inhibition of RBD in viral membrane identifying with ACE2. Finally, EGCG can interfere with the viral start replication by suppressing Mpro activity, although all these effects should be confirmed in vivo. A set of experiments evaluated the in vivo distribution of EGCG in human bodies [74] [75] [76] [77] [78] [79] and data showed that the values of EGCG concentration in the colon and intestine were higher than most of the concentrations necessary to promote 3CL protease required to effectively 3CL protease inhibition. More pre-clinical studies, clinical trials and epidemiological analysis will be extremely needed to validate EGCG anti-COVID-19 applications. EGCG and its stable lipophilic derivatives could also be potential prophylactic as well as therapeutic agents looking at their properties to dock at various active sites of SARS-CoV -2. Results from these studies will shed light on the role of the EGCG and the underlying molecular mechanisms for the treatment of SARS-CoV-2 infection. However, based on the current results published in the literature, it is not possible to say at all that EGCG can be considered as an election therapeutic drug for Covid-19. Due to the absence of specificity, EGCG could bind to other proteins present in the human body, thus provoking side-effects. EGGC After extensive studies on EGGC and other similar polyphenols regarding their specificity, activity, bioavailability and safety, there can be considerations on their use in the treatment of viral infections including COVID-19. Potential antiviral drugs for SARS-Cov-2 treatment: preclinical findings and ongoing clinical research A new coronavirus associated with human respiratory disease in China transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics An overview of current COVID-19 vaccine platforms Remdesivir and COVID-19 infection, therapeutic benefits or unnecessary risks? COVE Study Group. 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Clinical outcomes, patient safety, and programs for the development and effective, safe, and sustained use of medicines are a feature of the journal, which has also been accepted for indexing on PubMed Central. The manuscript management system is completely online and includes a very quick and fair peer-review system We are grateful to Dr. Alessandra Trocino and Mrs. Cristina Romano from the National Cancer Institute of Naples for providing excellent bibliographic service and assistance. Sabrina Bimonte and Cira Antonietta Forte are co-first authors of this study. Marco Cascella and Arturo Cuomo are co-last authors of this study. All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval for the version to be published, and agree to be accountable for all aspects of the work. The authors report no conflicts of interest in this work.