The Interaction of Antiviral Drugs with SARS-Cov-2 3CL Protease

SARS COV2 is one of the most destructive pandemics the world has faced and led to extreme economic losses. For its clinical therapy, SARS-COV-2 3CL Protease (3CLpro) is considered a target because of its crucial role in replication. Inhibition of this 3CLpro can lead to a decrease in viral load and infection. Different studies used various compounds and tested their inhibiting activity. Among them, flavonoids, serine derivatives, Chalcones, and alpha-keto amides were proven to have inhibitory effects. Many in-vitro tests were done to check the binding and inhibition abilities of such compounds. In vivo, some studies are done, but more is needed to prove this discovery. As far as research is concerned, therapeutic drugs against COVID-19 can be made by using such inhibitors. More in vivo studies and animal model experimentation should be done to confirm the findings.Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Computational molecular interaction between SARS-CoV-2 main protease and theaflavin digallate using free energy perturbation and molecular dynamics.

Our objective was to identify the molecule which can inhibit SARS-CoV-2 main protease and can be easily procured. Natural products may provide such molecules and can supplement the current custom chemical synthesis-based drug discovery for this objective. A combination of docking approaches, scoring functions, classical molecular dynamic simulation, binding pose metadynamics, and free energy perturbation calculations have been employed in this study. Theaflavin digallate has been observed in top-scoring compounds after the three independent virtual screening simulations of 598435 compounds (unique 27256 chemical entities). The main protease-theaflavin digallate complex interacts with critical active site residues of the main protease in molecular dynamics simulation independent of the explored computational framework, simulation time, initial structure, and force field used. Theaflavin digallate forms approximately three hydrogen bonds with Glutamate166 of main protease, primarily through hydroxyl groups in the benzene ring of benzo(7)annulen-6-one, along with other critical residues. Glu166 is the most critical amino acid for main protease dimerization, which is necessary for catalytic activity. The estimated binding free energy, calculated by Amber and Schrodinger MMGBSA module, reflects a high binding free energy between theaflavin digallate and main protease. Binding pose metadynamics simulation shows the highly persistent H-bond and a stable pose for the theaflavin digallate-main protease complex. Using method control, experimental controls, and test set, alchemical transformation studies confirm high relative binding free energy of theaflavin digallate with the main protease. Computational molecular interaction suggests that theaflavin digallate can inhibit the main protease of SARS-CoV-2.

Characterization in silico of bioactive compound in tea plant as a potentials inhibitor of SARS-CoV-2 Mpro

One of the screenings of the chemical structure that has the potential as an active major protease (Mpro) inhibitor in SARS-CoV-2 is bioactive compounds, such as oolonghomobisflavan-A, theaflavin-3-O-gallate, and theaflavin (TF). These bioactive compounds are main components of catechin oxidation, which contribute color, taste, and aroma to black tea. Enzymatic oxidation events in black tea processing have started at the beginning of the mill. In silico studies of active site Mpro as an inhibitor of SARS-CoV-2 were conducted using Protein Data Bank from a web platform. This analysis was carried out using the AutoDock Vina software integrated with PyRx 0.8. The molecular docking results were visualized in 3D and 2D with the BIOVIA Discovery Studio software with the result that amino acid residues and chemical bonds formed were visible, indicating the binding site of a target protein. The production of bioactive compounds through the tea fermentation process accelerated the oxidation rate of catechins into the contained bioactive compounds, which was analyzed using a spectrophotometer with a wavelength of 380 nm. Bioactive compound analysis used the response surface methodology. The results of docking the oolonghomobisflavan compound with Mpro indicated the highest binding affinity, namely −8.0 kcal/mol;however, the oolonghomobisflavan compound with Mpro did not show the same interaction as the control. On the contrary, for the docking of theaflavin-3’-Ogallate with Mpro, the binding affinity was −6.3 kcal/mol and showed the same interaction with the control, namely, LysA:137, where the compound formed hydrogen bonds, and analysis of the selected compound was carried out on the theaflavin-3’-O-gallate compound. The optimal operating conditions for the extraction process were at a flow rate of 17.65 l/minute with a fermentation time of 50 minutes, which produced a maximum theaflavin level of 0.938%. © 2022 Mohamad Endy Yulianto et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Optimization of UV-photo fermentation conditions theaflavin from tea leaves (Camellia sinensis) using response surface methodology (RSM) as inhibitor in SARS-CoV-2

Theaflavin (TF) is a component of fermented (enzymatic oxidation) catechin compounds synthesized during tea leaf fermentation, giving a golden yellow color, taste, and aroma to black tea. Theaflavins, which are rich in antioxidants, can treat cancer, obesity, diabetes and are potential as an inhibitor in SARS-CoV-2. Photo fermentation using ultraviolet (UV) has the advantage of penetrating the stoma cell wall in tea leaves and accelerating the oxidation of tea leaves that have gone through the milling process before the fermentation stage. This study aimed to optimize the photo fermentation process of theaflavin compounds from fresh tea leaves through response surface methodology (RSM). The highest theaflavin was obtained at a flow rate of 6 L/minute and a long irradiation time of 55 min, with a theaflavin content of 0.6705%. RSM states that the oxygen flow rate is the most influential factor with an R-Square value of 0.60814 means only 60.814% variation in data can be described by the model. (C) 2022 The Authors. Published by Elsevier Ltd.

Investigation of the Azorean Camellia sinensis Processing Conditions to Maximize the Theaflavin 3,3'-di-O-Gallate Content as a Potential Antiviral Compound.

The molecular constituents of Camellia sinensis, in particular epigallocatechin-3-O-gallate (EGCG) and, more remarkably, the galloylated theaflavins, mainly theaflavin-3,3'-di-O-gallate (TF-3,3'-DG), have been reported to inhibit SARS-CoV-2 3-chymotrypsin-like protease (3CLpro), an enzyme required for the cleavage of its polyproteins, to produce vital individual functional proteins for viral cell replication. Our results for total catechin content revealed the values of 174.72, 200.90, and 211.75 mg/g dry weight (DW) in spring, and the values of 183.59, 191.36, and 215.09 mg/g DW in summer, for tea plantation zones 1, 2, and 3, respectively. For the TF-3,3'-DG content, the values of 2.68, 1.13, and 3.72 mg/g DW were observed in spring, and the values of 3.78, 2.06, and 8.91 mg/g DW in summer for zones 1, 2, and 3, respectively. In the same zone, different contents of TF-3,3'-DG were observed across plucking months of April, June, and August, with values of 1.13, 2.77, and 4.18 mg/g DW, respectively, showing higher values in summer. Different values of TF-3,3'-DG contents were also observed in the same tea plantation zone but from different plant parts, revealing higher values in the bud and the first and second leaves (3.62 mg/g DW) and lower values in the third and fourth leaves (1.14 mg/g DW). The TF-3,3'-DG content increased from 3.31 to 4.98 mg/g DW with increased fermentation time from 1 to 3 h, respectively, and increased for lower temperature and longer fermentation time. The aim of this study was to investigate the processing conditions that lead to maximum TF-3,3'-DG content and, given its potential impact as an inhibitor of the 3CLpro enzyme, to create a novel antiviral Azorean black tea.

INTERACTION BETWEEN ACE 2 AND SARS-COV2, AND USE OF EGCG AND THEAFLAVIN TO TREAT COVID 19 IN INITIAL PHASES

Covid Virus particles engage with host cells via the ACE-2 and GRP78 receptors, transferring the genome particle to the host cell and transforming it into a replicating machine. RdRP is a key protein in the replication mechanism of all RNA viruses. 3CLpro is a cleavage enzyme that breaks down polyproteins into non-structural polyproteins. All four elements of the Covid viral particle are required for its propagation and action, and blocking any one of them can shut down the entire system. EGCG and Theaflavins are flavonoids that block virus particles from attaching to the host cell's ACE-2 and GRP78 receptors, preventing the genome from being transferred into the cell. EGCG binds to 3CLpro with a molecular docking value of 11.7, while TF3 has a docking score of 10.574, indicating that it prevents host cell contact. TF binds to RdRP with a binding energy of 9.11 kcal/mol, implying that RdRP activities are interfered with. Furthermore, these flavonoids have anti-inflammatory properties and reduce the action of cytokines, which can cause serious respiratory difficulties. Except these two there are many others flavonoids which possess anti-inflammatory and anti-viral properties. All of these data suggest that flavonoids could be a useful treatment for SARS-CoV19;however, the issue of stability and bioavailability arises because it is unstable at lungs pH.

Effects of theaflavin-gallate in-silico binding with different proteins of SARS-CoV-2 and host inflammation and vasoregulations referring an experimental rat-lung injury.

Background SARS-CoV-2 claimed 5,209,104 lives, infected 260,997,910 individuals, globally. Infection is caused due to exposure or susceptibility; deaths occur due to age,comorbidity,higher-viral-load, immuno-suppression, inflammation, and multi-organ failure. Theaflavin-gallate, the major black tea component, showed previous evidence to inhibit HIV-1. Purpose As theaflavin-gallate prevents experimental rat-lung injury, the study of inhibitory effects of theaflavin-gallate was done, on SARS-CoV-2proteins and various host proteins related to some adverse effects in COVID-19 patients. Study Design Currently, some prospective phytochemical, black-tea (Camellia-sinensis) extract (BTE) was initially tested in vivo in strong oxidant-mutagen arsenic-induced model rat lung injury similar to that of COVID-19 manifestations like severe inflammation, oxidative stress, lung tissue degenerations, and apoptotic death. In silico, extensive bioinformatics and molecular docking experiments were performed on all catechin or theaflavin derivatives of C. sinensis, and finally theaflavin-3'-O-gallate (TFMG) were screened for blocking or inactivation of several proteins of SARS CoV-2 and host adversely-acting proteins or factors. Methods In vivo experiments in DNA stability (ladder, comet assay), free radicals attack (malondialdehyde; MDA, superoxide dismutase SOD, catalase gel-zymogram assay), extra cellular matrix damage (matrix metalloprotease; MMP2and9 zymogram assay) and inflammation (TNF-α, ELISA). In silico experiments- molecular docking by AutoDock-Patchdock analysis, Surface Topology Calculation by CASTp, Grid-value calculation, and Ramachandran Plot study. Results The BTE showed strong protection of lung DNA and cell-matrix by decreasing MMPs, TNF-α, and free radicals, the same factors affecting COVID-19 patients. In silico data suggest that TFMG significantly blocked the entry, exit, and amino acids at catalytic active-site of more than thirty proteins including viral (nsp1,nsp2,Mainpro,∼-9.0 kcal/mol) and host inflammatory, oxidants, apoptotic, vaso-destabilizer molecules (FAS, CD40R, BCL2, TLR2, ∼ -10 and ACE1or2 ∼ -9.0 and AT1or2∼ -7.5 kcal/mol and more). When the binding energy of TFMG ranged from -7 to -11.7 kcal/mol(average -9.0) the same for hydroxy­Chloroquine ranged (-2.5 to -7 average -4.5) and dexamethasone (-3.0 to -6.0, average -4.0 kcal/mol). Conclusions TFMG has some novel physicochemical or structural properties like (ACE values of binding to all tested proteins, -300 to -625), (for TFMG H-bond acceptor or donor: 15/10, for TFDG 20/13). Their topological-polar-surface-area (264Ų and 351Ų) and travel depth/height; 17.0/9.6 Å and 15.4/11.3 Å, respectively) were more potent than other compounds. Conclusively, the efficacy of TFMG may be further verified.

Molecular docking approach of natural compound from herbal medicine in java against severe acute respiratory syndrome coronavirus-2 receptor

BACKGROUND: Indonesia’s diversity of natural resources presents an intriguing opportunity for the exploration of potential herbal medicines. Numerous compounds, both purified and crude, have been reported to exhibit antiviral activity. The angiotensin-converting enzyme 2 (ACE-2) receptor may be a therapeutic target for severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. We used a search engine to search for herbal medicines with ACE-2 inhibitory activity to predict the potential inhibition of natural compounds (i.e., theaflavin, deoxypodophyllotoxin, gallocatechin, allicin, quercetin, annonamine, Curcumin, 6-gingerol, and cucurbitacin B) to SARS-CoV2–ACE-2 complex. AIM: This research conducted to search potential compound against COVID-19 receptor. METHODS: We performed molecular docking analysis using the ACE-2 receptor protein target from Protein Data Bank. Protein stabilization was carried out to adjust to the body’s physiology, carried out using Pymol by removing water atoms and adding hydrogen atoms. Ligands of active compounds from natural resources were selected and downloaded from the PubChem database, then optimized by Pymol software. RESULTS: The complexes of the tested ligands compounds and ACE-2 receptors, which have a bond strength smaller than the control, were selected for analysis. It was discovered in this study that the aflavin, deoxypodophyllotoxin, gallocatechin, curcumin, and cucurbitacin B had a higher bond affinity than the control ligands XX5. This binding pocket interaction is also the same for all ligands. CONCLUSION: It is hoped that this study would serve as a starting point for future research into possible treatment candidates for SARS-CoV-2.

Severe Acute Respiratory Syndrome Coronavirus-2 Inactivation Activity of the Polyphenol-Rich Tea Leaf Extract with Concentrated Theaflavins and Other Virucidal Catechins.

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is producing a large number of infections and deaths globally, the development of supportive and auxiliary treatments is attracting increasing attention. Here, we evaluated SARS-CoV-2-inactivation activity of the polyphenol-rich tea leaf extract TY-1 containing concentrated theaflavins and other virucidal catechins. The TY-1 was mixed with SARS-CoV-2 solution, and its virucidal activity was evaluated. To evaluate the inhibition activity of TY-1 in SARS-CoV-2 infection, TY-1 was co-added with SARS-CoV-2 into cell culture media. After 1 h of incubation, the cell culture medium was replaced, and the cells were further incubated in the absence of TY-1. The viral titers were then evaluated. To evaluate the impacts of TY-1 on viral proteins and genome, TY-1-treated SARS-CoV-2 structural proteins and viral RNA were analyzed using western blotting and real-time RT-PCR, respectively. TY-1 showed time- and concentration-dependent virucidal activity. TY-1 inhibited SARS-CoV-2 infection of cells. The results of western blotting and real-time RT-PCR suggested that TY-1 induced structural change in the S2 subunit of the S protein and viral genome destruction, respectively. Our findings provided basic insights in vitro into the possible value of TY-1 as a virucidal agent, which could enhance the current SARS-CoV-2 control measures.

GB-2 blocking the interaction between ACE2 and wild type and mutation of spike protein of SARS-CoV-2.

Since the start of the outbreak of coronavirus disease 2019 in Wuhan, China, there have been more than 150 million confirmed cases of the disease reported to the World Health Organization. The beta variant (B.1.351 lineage), the mutation lineages of SARS-CoV-2, had increase transmissibility and resistance to neutralizing antibodies due to multiple mutations in the spike protein. N501Y, K417N and E484K, in the receptor binding domain (RBD) region may induce a conformational change of the spike protein and subsequently increase the infectivity of the beta variant. The L452R mutation in the epsilon variant (the B.1.427/B.1.429 variants) also reduced neutralizing activity of monoclonal antibodies. In this study, we discovered that 300 µg/mL GB-2, from Tian Shang Sheng Mu of Chiayi Puzi Peitian Temple, can inhibit the binding between ACE2 and wild-type (Wuhan type) RBD spike protein. GB-2 can inhibit the binding between ACE2 and RBD with K417N-E484K-N501Y mutation in a dose-dependent manner. GB-2 inhibited the binding between ACE2 and the RBD with a single mutation (K417N or N501Y or L452R) except the E484K mutation. In the compositions of GB-2, glycyrrhiza uralensis Fisch. ex DC., theaflavin and (+)-catechin cannot inhibit the binding between ACE2 and wild-type RBD spike protein. Theaflavin 3-gallate can inhibit the binding between ACE2 and wild-type RBD spike protein. Our results suggest that GB-2 could be a potential candidate for the prophylaxis of some SARS-CoV-2 variants infection in the further clinical study because of its inhibition of binding between ACE2 and RBD with K417N-E484K-N501Y mutations or L452R mutation.

Virtual screenings of the bioactive constituents of tea, prickly chaff, catechu, lemon, black pepper, and synthetic compounds with the main protease (Mpro) and human angiotensin-converting enzyme 2 (ACE 2) of SARS-CoV-2.

BACKGROUND: COVID-19 has mutation capability, and there are no specific drug therapies that are available to fight or inhibit the proteins of this virus. The present study aims to investigate the binding affinity of the bioactive and synthetic compounds with the main protease (Mpro) enzymes and angiotensin-converting enzyme 2 (ACE 2) by computational approach. PASS prediction, pharmacokinetics, and toxicological properties prediction studies were performed through the Google PASS prediction and Swiss ADME/T website. Besides, molecular docking studies were accomplished by BIOVIA Discovery Studio 2020, UCSF Chimera, and PyRx autodock vina. RESULTS: The docking scores were inferred and the selected compounds showed results varying from -3.2 to -9.8 (kcal/mol). Theaflavin scored the highest docking score to the 5REB, 6VW1, and 1R42 enzymes and showed the binding affinity as -6.3 kcal/mol, -9.8 kcal/mol, and -8.6 kcal/mol, respectively. Again, kaempferol showed the best binding affinity to the 7BQY (-7.1 kcal/mol) and 6Y2FB (-6.6 kcal/mol) enzymes. All the chemical constituents showed better probability in action in pass prediction analysis. Besides, no ligands (except theaflavin) have any conflict with Lipinski's rules of five, which authorized the drug probability of these ligands. CONCLUSION: Therefore, the selected compounds could be considered a potential herbal treatment source against SARS-CoV-2.

Significant Inactivation of SARS-CoV-2 In Vitro by a Green Tea Catechin, a Catechin-Derivative, and Black Tea Galloylated Theaflavins.

Potential effects of tea and its constituents on SARS-CoV-2 infection were assessed in vitro. Infectivity of SARS-CoV-2 was decreased to 1/100 to undetectable levels after a treatment with black tea, green tea, roasted green tea, or oolong tea for 1 min. An addition of (-) epigallocatechin gallate (EGCG) significantly inactivated SARS-CoV-2, while the same concentration of theasinensin A (TSA) and galloylated theaflavins including theaflavin 3,3'-di-O-gallate (TFDG) had more remarkable anti-viral activities. EGCG, TSA, and TFDG at 1 mM, 40 µM, and 60 µM, respectively, which are comparable to the concentrations of these compounds in tea beverages, significantly reduced infectivity of the virus, viral RNA replication in cells, and secondary virus production from the cells. EGCG, TSA, and TFDG significantly inhibited interaction between recombinant ACE2 and RBD of S protein. These results suggest potential usefulness of tea in prevention of person-to-person transmission of the novel coronavirus.

Rapid Inactivation In Vitro of SARS-CoV-2 in Saliva by Black Tea and Green Tea.

Saliva plays major roles in the human-to-human transmission of SARS-CoV-2. If the virus in saliva in SARS-CoV-2-infected individuals can be rapidly and efficiently inactivated by a beverage, the ingestion of the beverage may attenuate the spread of virus infection within a population. Recently, we reported that SARS-CoV-2 was significantly inactivated by treatment with black tea, green tea, roasted green tea and oolong tea, as well as their constituents, (-) epigallocatechin gallate (EGCG), theasinensin A (TSA), and galloylated theaflavins. However, it remains unclear to what extent tea inactivates the virus present in saliva, because saliva contains various proteins, nitrogenous products, electrolytes, and so on, which could influence the antivirus effect of tea. Here, we assessed whether tea inactivated the SARS-CoV-2 which was added in human saliva. A virus was added in healthy human saliva in vitro, and after treatment with black tea or green tea, the infectivity of the virus was evaluated by TCID50 assays. The virus titer fell below the detectable level or less than 1/100 after treatment with black tea or green tea for 10 s. The black tea-treated virus less remarkably replicated in cells compared with the untreated virus. These findings suggest the possibility that the ingestion of tea may inactivate SARS-CoV-2 in saliva in infected individuals, although clinical studies are required to determine the intensity and duration of the anti-viral effect of tea in saliva in humans.

Black tea bioactives as inhibitors of multiple targets of SARS-CoV-2 (3CLpro, PLpro and RdRp): a virtual screening and molecular dynamic simulation study.

The global pandemic due to the novel Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) has taken more than a million lives. Lack of definitive vaccine/drugs against this highly contagious virus has accelerated exploratory research on novel natural and synthetic inhibitors. Tea is a rich source of bioactives and known to have antiviral properties. In this study, an in silico strategy involving ADMET property screening, receptor-ligand docking and molecular dynamic (MD) simulation was employed to screen potential tea bio-active inhibitors against three selected targets (RdRp, 3CLpro and PLpro) of SARS-CoV-2. Among the 70 tea bioactives screened, theaflavin 3,3'-di-gallate (TF3), Procyanidin B2 and Theaflavin 3-gallate (TF2a) exhibited highest binding affinities towards RdRp, 3CLpro/Mpro and PLpro targets of SARS-CoV-2 with low docking scores of -14.92, -11.68 and -10.90 kcal/mol, respectively. All of them showed a substantial number of hydrogen bonds along with other interactions in and around the active sites. Interestingly, the top bioactives in our study showed higher binding affinities compared with known antiviral drugs. Further, the top protein-ligand complexes showed less conformational changes during binding when subjected to MD simulation for 100 nanoseconds. The MMPBSA results revealed that RdRp-TF3, 3CLpro-Procyanidin B2 and PLpro-TF2a complexes were stable with binding free energies of -93.59 ± 43.97, -139.78 ± 16.51 and -96.88 ± 25.39 kJ/mol, respectively. Our results suggest that theaflavin 3,3'-digallate, Theaflavin 3-gallate and Procyanidin B2 found in black tea have the potential to act as inhibitors for selected targets of SARS-CoV-2 and can be considered as drug candidates in future studies against COVID-19.

Potential Simultaneous Inhibitors of Angiotensin-Converting Enzyme 2 and Transmembrane Protease, Serine 2.

Outbreak of coronavirus disease 2019 occurred in Wuhan and has rapidly spread to almost all parts of world. GB-1, the herbal formula from Tian Shang Sheng Mu of Chiayi Puzi Peitian Temple, is used for the prophylaxis of SARS-CoV-2 in Taiwan. In this study, we investigated that the effect of GB-1 and the index compounds of GB-1 on the ACE2 and TMPRSS2 expression through in vitro and in vivo study. In our result, GB-1 can inhibit ACE2 and TMPRSS2 protein expression in HepG2 cells, 293T cells, and Caco-2 cells without cytotoxicity. For the mouse model, GB-1 treatment could decrease ACE2 and TMPRSS2 expression levels of the lung and kidney tissue without adverse effects, including nephrotoxicity and hepatotoxicity. In the compositions of GB-1, 0.5-1 mg/ml of Glycyrrhiza uralensis Fisch. ex DC. extract could not inhibit ACE2 mRNA and protein expression in HepG2 cells. In addition, theaflavin-3-gallate could inhibit protein expression of ACE2 and TMPRSS2 without significant cytotoxicity. Our results suggest that GB-1 and theaflavin-3-gallate could act as potential candidates for prophylaxis or treatment of SARS-CoV-2 infection through inhibiting protein expression of ACE2 and TMPRSS2 for the further study.

Molecular Descriptors of Some Chemicals that Prevent COVID-19.

BACKGROUND: Topological index is a numerical molecular descriptor that plays an important role in structure-property/structure-activity modeling. A large number of works on multiplicative degree based indices have been developed. However, no attention is paid to investigating their chemical significance. Investigation of the chemical importance of such indices is needed. The computation of topological indices for different chemical structures and networks is a current topic of interest in mathematical chemistry. OBJECTIVE: The objective of the present work is to examine the usefulness of the multiplicative degree based indices in quantitative structure property/activity relationship modeling. In addition, we intend to compute the indices for some anti-COVID-19 chemicals. MATERIALS AND METHODS: The regression analysis for octane data set is performed using MATLAB and Excel to check the predictability of the indices. The sensitivity test is conducted to examine the isomer discrimination ability. To study the indices for chemical structures preventing COVID-19, different combinatorial computation methods are utilized. RESULTS AND DISCUSSION: The regression models governing the structural dependence of different properties and activities are derived. The supremacy of the indices as useful molecular descriptors compared to some well-known and most used descriptors is established. Explicit expressions of the indices for hydroxychloroquine, remdesivir (GS-5734) and theaflavin are obtained. CONCLUSION: As the indices are shown to have remarkable efficiency in quantitative structure property/activity relationship modeling and isomer discrimination, the outcomes can predict different properties and activities of the chemicals under consideration.

GB-2 inhibits ACE2 and TMPRSS2 expression: In vivo and in vitro studies.

After the first case of Coronavirus disease 2019 (COVID-19) was reported in Wuhan, COVID-19 has rapidly spread to almost all parts of world. Angiotensin converting enzyme 2 (ACE2) receptor can bind to spike protein of SARS-CoV-2. Then, the spike protein of SARS-CoV-2 can be cleaved and activated by transmembrane protease, serine 2 (TMPRSS2) of the host cells for SARS-CoV-2 infection. Therefore, ACE2 and TMPRSS2 are potential antiviral targets for treatment of prevention of SARS-CoV-2 infection. In this study, we discovered that 10-250 µg/mL of GB-2, from Tian Shang Sheng Mu of Chiayi Puzi Peitian Temple, can inhibit ACE2 mRNA expression and ACE2 and TMPRSS2 protein expression in HepG2 and 293 T cells without cytotoxicity. GB-2 treatment could decrease ACE2 and TMPRSS2 expression level of lung tissue and kidney tissue without adverse effects, including nephrotoxicity and hepatotoxicity, in animal model. In the compositions of GB-2, we discovered that 50 µg/mL of theaflavin could inhibit protein expression of ACE2 and TMPRSS2. Theaflavin could inhibit the mRNA expression of ACE2. In conclusion, our results suggest that GB-2 and theaflavin could act as potential compounds for ACE2 and TMPRSS2 inhibitors in the further clinical study.

Antiviral activity of green tea and black tea polyphenols in prophylaxis and treatment of COVID-19: A review.

BACKGROUND: The rapid spread of novel coronavirus called SARS-CoV-2 or nCoV has caused countries all over the world to impose lockdowns and undertake stringent preventive measures. This new positive-sense single-stranded RNA strain of coronavirus spreads through droplets of saliva and nasal discharge. PURPOSE: US FDA has authorized the emergency use of Remdesivir looking at the increasing number of cases of COVID-19, however there is still no drug approved to treat COVID-19. An alternative way of treatment could be the use of naturally derived molecules with known antiviral properties. METHOD: We reviewed the antiviral activities of two polyphenols derived from tea, epigallocatechin-3-gallate (EGCG) from green tea and theaflavins from black tea. Both green tea and black tea polyphenols have been reported to exhibit antiviral activities against various viruses, especially positive-sense single-stranded RNA viruses. RESULTS: Recent studies have revealed the possible binding sites present on SARS-CoV-2 and studied their interactions with tea polyphenols. EGCG and theaflavins, especially theaflavin-3,3'-digallate (TF3) have shown a significant interaction with the receptors under consideration in this review. Some docking studies further emphasize on the activity of these polyphenols against COVID-19. CONCLUSION: This review summarizes the available reports and evidences which support the use of tea polyphenols as potential candidates in prophylaxis and treatment of COVID-19.

The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase.

An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan and it has rapidly spread to almost all parts of the world. For coronaviruses, RNA-dependent RNA polymerase (RdRp) is an important polymerase that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target. In this study, we screened these chemical structures from traditional Chinese medicinal compounds proven to show antiviral activity in severe acute respiratory syndrome coronavirus (SARS-CoV) and the similar chemical structures through a molecular docking study to target RdRp of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). We found that theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS-CoV-2 (-9.11 kcal/mol), SARS-CoV (-8.03 kcal/mol), and MERS-CoV (-8.26 kcal/mol) from idock. To confirm the result, we discovered that theaflavin has lower binding energy of -8.8 kcal/mol when it docks in the catalytic pocket of SARS-CoV-2 RdRp by using the Blind Docking server. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were found between theaflavin and RdRp. Moreover, one π-cation interaction was formed between theaflavin and Arg553 from the Blind Docking server. Our results suggest that theaflavin could be a potential SARS-CoV-2 RdRp inhibitor for further study.