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Kaempferol Derivatives as Antiviral Drugs against the 3a Channel Protein of Coronavirus
Abstract
The protein coded by the open-reading-frame 3a of SARS coronavirus has been demonstrated to form a cation-selective channel that may become expressed in the infected cell. The activity of the channel is involved in the mechanism of virus release. Drugs that inhibit the ion channel can, therefore, inhibit virus release, and they could be a source for development of novel therapeutic antiviral agents. Various drugs found in Chinese herbs that are well known as anticancer agents also have an antiviral potency. Here we tested the flavonols kaempferol, kaempferol glycosides, and acylated kaempferol glucoside derivatives with respect to their potency to block the 3a channel. We used the Xenopus oocyte with a heterologously expressed 3a protein as a model system to test the efficacy of the flavonols. Some of these drugs turned out to be potent inhibitors of the 3a channel. The most effective one was the glycoside juglanin (carrying an arabinose residue) with an IC50 value of 2.3 µM for inhibition of the 3a-mediated current. Kaempferol derivatives with rhamnose residue also seem to be quite effective. We suggest that viral ion channels, in general, may be a good target for the development of antiviral agents, and that, in particular, kaempferol glycosides are good candidates for 3a channel proteins of coronaviruses.
... In search of potent antiviral agents, naturally occurring compounds have always been admired because of their structural diversity, where kaempferol is one of the potent candidates. Kaempferol is a phytoestrogen and has a therapeutic advantage against COVID-19 due to its antiviral, antioxidant, anti-inflammatory, and anti-immune-modulatory properties [9], comprehensive implementation against CHIKV has not yet not been established. This phytoestrogen potentially inhibits the replication of the main protease of SARS-CoV-2 (3CLpro) [10], herpes simplex virus (HSV) type-1, the rotavirus [11,12], and pseudorabies virus [13] replication among other pathogens. ...
... Although the causal virus is new, reported cases of COVID-19 have grown dramatically over time. Researchers have previously revealed that while kaempferol has potential effects on the SARS virus [9], the mechanism of kaempferol against COVID-19 and CHIK remains unknown. Here, we investigated bioinformatics and network pharmacology approaches of kaempferol in COVID-19/CHK to uncover common biological targets and signaling pathways associated with diseases. ...
... Studies in vitro and in vivo revealed that kaempferol has immunomodulatory effects and inhibits NF-kB and MAP kinase phosphorylation [69]. When tested in cells infected cells, kaempferol inhibited protein kinase B and phosphorylated protein kinase [70] and blocked a specific channel (3a channel) [9]. Reactive oxygen species, inducible nitric oxide synthase production, pro-inflammatory mediators including TNF-, IL-1, IL-1, IL-6 and IL-10, as well as chemokines were decreased mainly through kaempferol and quercetin intervention [14]. ...
Chikungunya (CHIK) patients may be vulnerable to coronavirus disease (COVID-19). However, presently there are no anti-COVID-19/CHIK therapeutic alternatives available. The purpose of this research was to determine the pharmacological mechanism through which kaempferol functions in the treatment of COVID-19-associated CHIK co-infection. We have used a series of network pharmacology and computational analysis-based techniques to decipher and define the binding capacity, biological functions, pharmacological targets, and treatment processes in COVID-19-mediated CHIK co-infection. We identified key therapeutic targets for COVID-19/CHIK, including TP53, MAPK1, MAPK3, MAPK8, TNF, IL6 and NFKB1. Gene ontology, molecular and upstream pathway analysis of kaempferol against COVID-19 and CHIK showed that DEGs were confined mainly to the cytokine-mediated signalling pathway, MAP kinase activity, negative regulation of the apoptotic process, lipid and atherosclerosis, TNF signalling pathway, hepatitis B, toll-like receptor signaling, IL-17 and IL-18 signaling pathways. The study of the gene regulatory network revealed several significant TFs including KLF16, GATA2, YY1 and FOXC1 and miRNAs such as let-7b-5p, mir-16-5p, mir-34a-5p, and mir-155-5p that target differential-expressed genes (DEG). According to the molecular coupling results, kaempferol exhibited a high affinity for 5 receptor proteins (TP53, MAPK1, MAPK3, MAPK8, and TNF) compared to control inhibitors. In combination, our results identified significant targets and pharmacological mechanisms of kaempferol in the treatment of COVID-19/CHIK and recommended that core targets be used as potential biomarkers against COVID-19/CHIK viruses. Before conducting clinical studies for the intervention of COVID-19 and CHIK, kaempferol might be evaluated in wet lab tests at the molecular level.
... In search of potent antiviral agents, naturally occurring compounds have always been admired because of their structural diversity, where kaempferol is one of the potent candidates. Kaempferol is a phytoestrogen and has a therapeutic advantage against COVID-19 due to its antiviral, antioxidant, anti-inflammatory, and anti-immune-modulatory properties [9], comprehensive implementation against CHIKV has not yet not been established. This phytoestrogen potentially inhibits the replication of the main protease of SARS-CoV-2 (3CLpro) [10], herpes simplex virus (HSV) type-1, the rotavirus [11,12], and pseudorabies virus [13] replication among other pathogens. ...
... Although the causal virus is new, reported cases of COVID-19 have grown dramatically over time. Researchers have previously revealed that while kaempferol has potential effects on the SARS virus [9], the mechanism of kaempferol against COVID-19 and CHIK remains unknown. Here, we investigated bioinformatics and network pharmacology approaches of kaempferol in COVID-19/CHK to uncover common biological targets and signaling pathways associated with diseases. ...
... Studies in vitro and in vivo revealed that kaempferol has immunomodulatory effects and inhibits NF-kB and MAP kinase phosphorylation [69]. When tested in cells infected cells, kaempferol inhibited protein kinase B and phosphorylated protein kinase [70] and blocked a specific channel (3a channel) [9]. Reactive oxygen species, inducible nitric oxide synthase production, pro-inflammatory mediators including TNF-, IL-1, IL-1, IL-6 and IL-10, as well as chemokines were decreased mainly through kaempferol and quercetin intervention [14]. ...
We have used a series of network pharmacology and computational analysis-based techniques to decipher and define the binding capacity, biological functions, pharmacological targets, and treatment processes in COVID-19-mediated CHIK co-infection. We identified key therapeutic targets for COVID-19/CHIK, including TP53, MAPK1, MAPK3, MAPK8, TNF, IL6 and NFKB1. Gene ontology, molecular and upstream pathway analysis of kaempferol against COVID-19 and CHIK showed that DEGs were confined mainly to the cytokine-mediated signalling pathway, MAP kinase activity, negative regulation of the apoptotic process, lipid and atheroscle-rosis, TNF signalling pathway, hepatitis B, toll-like receptor signaling, IL-17 and IL-18 signaling pathways. The study of the gene regulatory network revealed several significant TFs including KLF16, GATA2, YY1 and FOXC1 and miRNAs such as let-7b-5p, mir-16-5p, mir-34a-5p, and mir-155-5p that target differential-expressed genes (DEG). According to the molecular coupling results, kaempferol exhibited a high affinity for 5 receptor proteins
... The kaempferol glycoside juglanin, with an IC 50 value of 2.30 μM, was the most efficient in inhibiting the 3a-mediated current. Additionally, kaempferol derivatives containing rhamnose residue appear to be extremely effective, indicating that kaempferol glycosides are promising candidates for coronaviruses' 3a channel proteins [146]. ...
... With the exception of galangin, they all demonstrated highly effective antiviral activity against several infections. Clinical investigations specifically showed that kaempferol and quercetin have an antiviral effect against the SARS-COV-2 virus, which was the cause of the recent pandemic scenario [146]. Antidiabetic activities of these compounds were noteworthy, all of them was found to have strong antidiabetic activities, especially by decreasing glucose level, and insulin resistance as well as improving other diabetic parameters. ...
Flavonoids are organic compounds characterized by a range of phenolic structures, which are abundantly present in various natural sources such as fruits, vegetables, cereals, bark, roots, stems, flowers, tea, and wine. The health advantages of these natural substances are renowned, and initiatives are being taken to extract the flavonoids. Apigenin, galangin, hesperetin, kaempferol, myricetin, naringenin, and quercetin are the seven most common compounds belonging to this class. A thorough analysis of bibliographic records from reliable sources including Google Scholar, Web of Science, PubMed, ScienceDirect, MEDLINE, and others was done to learn more about the biological activities of these flavonoids. These flavonoids appear to have promising anti-diabetic, anti-inflammatory, antibacterial, antioxidant, antiviral, cytotoxic, and lipid-lowering activities, according to evidence from in vitro, in vivo, and clinical research. The review contains recent trends, therapeutical interventions, and futuristic aspects of flavonoids to treat several diseases like diabetes, inflammation, bacterial and viral infections, cancers, and cardiovascular diseases. However, this manuscript should be handy in future drug discovery. Despite these encouraging findings, a notable gap exists in clinical research, hindering a comprehensive understanding of the effects of flavonoids at both high and low concentrations on human health. Future investigations should prioritize exploring bioavailability, given the potential for high inter-individual variation. As a starting point for further study on these flavonoids, this review paper may promote identifying and creating innovative therapeutic uses.
... Some of the interactions and better binding affinities observed in this study are supported by reported antiviral activities of some of the molecules. For instance literature sources have elaborately reported on the antiviral activities of kaempferol (Schwarz et al., 2014), limonene (Astani and Schnitzler, 2014) and myricetin (Ortega et al., 2019) against coronavirus as well as herpes simplex virus. Similarly kolaviron a biflavonoid from G. kola has also been reported to display antiviral activity (Dongmo et al., 2019). ...
... The ProTox II evaluation showed that the key components in COVI-MXG which have been reported to have strong antiviral activities such as kaempferol (Schwarz et al., 2014), limonene (Astani and Schnitzler, 2014), myricetin (Ortega et al., 2019), and monoterpenes (γ-terpinene, α-pinene; 1, 8-cineole) (Astani et al., 2010) are inactive with respect to carcinogenicity, hepatotoxicity, mutagenicity, cytotoxicity and immunotoxicity. Similarly, kolaviron a biflavonoid from G. kola which is reported to have strong antiviral activities (Buba et al., 2016;Dongmo et al., 2019) and shows the highest binding affinity to the SARS-COV-2 target protein is inactive with respect to the parameters of the ProTox II evaluation. ...
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been identified as the agent
responsible for COVID-19 pandemic. Currently, no therapeutic agents have proven effective in
combating the virus. Managing the infection is mainly palliative in nature, involving infection prevention
strategies and supportive therapy anchored on drugs that practitioners have had previous usage
experience. Previously exploited therapeutic agents include antiviral and antimalarial agents
(remdesivir, hydroxychloroquine, chloroquine, lopinavir, umifenovir, favipiravir, and oseltamivir).
Micronutrients (zinc, selenium) have also been used. There are claims of herbal preparations that are
thought to be beneficial. The self-formulated herbal preparation, COVI-MXG contains a unique
combination of five plants. In silico methodologies were used to evaluate the phytochemical
constituents. This was to determine possible antiviral activity, safety during usage and pharmacokinetic
properties. Docking studies of selected phytochemical compounds in COVI-MXG evaluated against the
COVID-19 viral protein target showed binding affinity ranging from -8.1 to -4.2 Kcal/mol. Blood brain
barrier permeability and gastrointestinal absorption rates varied to different degrees. Toxicity class
varied from 3 to 5. LD50 values were relatively high. COVI-MXG contained phytochemical compounds
with better binding affinities for SARS-CoV-2 protein (7BV2) than currently employed therapeutic agents
(remdesivivr, hydroxychloroquine, chloroquine, lopinavinavir, umifenovir, favipiravir, oseltamivir) which
were included in the virtual screening. The phytochemical compounds showed excellent interactions
with amino acid residues in the catalytic nsp12 domain. This excellent interaction is likely to result in a
better therapeutic outcome in the management of COVID-19. In silico predictions for stability and
pharmacokinetic parameters predicted that the formulation can be administered orally.
Key words: COVID-19, SAR-CoV-2, COVI-MXG, zinc.
... In addition, the viroporin channel E protein of SARS-CoV -2 can also be inhibited by flavonoids such as quercetin and EGCG [20]. Hitherto, flavonoid kaempferol found in herbs have shown to combat viral infections such as SARS-COV-2, by inhibiting 3a channels involved in viral life-cycle [21]. ...
... In literature and online search, the achene of the Great Burdock and honeysuckle flower were selected as therapy herbs, and gene lists and their targets were determined from herb database (http://herb.ac.cn/) that includes information of the extracted and published compounds. Target genes from the herbs database were further compared with MPXV gene datasets [20,21] that indicated the infection induced changes in host cell gene expression. For the identification and common genes selection purpose, Venn diagrams were constructed by (https://bioinfogp.cnb.csic.es/tools/venny/). ...
Background:
Monkeypox is an orthopoxvirus that is responsible for zoonotic infections in humans. The virus has recently spread rapidly and the WHO has listed it as an international public health emergency of concern.
Research design and methods:
Here, we used network analysis and gene enrichment protocols and analyzed datasets of MPXV infection that induced host cell gene expression list and subsequently mapped them against two herbal target gene lists which highlighted considerable coherence in pharmacological attributes with COVID-19. Molecular docking and simulation were performed for the screened compounds.
Results:
Our results identified β-carotene and kaempferol possessing tremendous ability against the MPXV PLD protein. Both compounds were subjected to each of 100 ns molecular dynamics simulation and were found native to the PLD pocket. MM-PB (GB) SA analyses indicated -25.4, -40.1 kcal/mol and -17.2, -26.4kcal/mol of ΔGbind to the active pocket of PLD. Our data suggest the adaptive nature of the MPXV PLD active pocket toward hydrophobic inhibitors.
Conclusion:
These results will be of high importance for the viral researchers to be tested in wet lab settings in designing potential inhibitors.
... Kaempferol and its derivatives has been reported to have broad antiviral activities against influenza virus, Japanese encephalitis virus, dengue virus, human immunodeficiency virus, hepatitis B virus and coronaviruses [39,40,52]. For SARS-CoV-2, several in silico studies have shown strong binding of Kaempferol with Mpro [52,53]. ...
... Kaempferol and its derivatives has been reported to have broad antiviral activities against influenza virus, Japanese encephalitis virus, dengue virus, human immunodeficiency virus, hepatitis B virus and coronaviruses [39,40,52]. For SARS-CoV-2, several in silico studies have shown strong binding of Kaempferol with Mpro [52,53]. In lie with this, we also show strong binding affinity of Rutin with Mpro but not with other proteins of SARS-CoV-2. ...
Aim
Structure-based identification of natural compounds against SARS-CoV-2, Delta and Omicron target proteins.
Materials & methods
Several known antiviral natural compounds were subjected to molecular docking and MD simulation against SARS-CoV-2 Mpro, Helicase and Spike, including Delta and Omicron Spikes.
Results
Of the docked ligands, 20 selected for each complex exhibited overall good binding affinities (-7.79 to -5.06 kcal/mol) with acceptable physiochemistry following Lipinski's rule. Finally, two best ligands from each complex upon simulation showed structural stability and compactness.
Conclusion
Quercetin-3-acetyl-glucoside, Rutin, Kaempferol, Catechin, Orientin, Obetrioside and Neridienone A were identified as potential inhibitors of SARS-CoV-2 Mpro, Helicase and Spike, while Orientin and Obetrioside also showed good binding affinities with Omicron Spike. Catechin and Neridienone A formed stable complexes with Delta Spike.
... Membrane expression was reduced for a mutant that showed less current when expressed in HEK-293 cells [19]. Expression of the wild-type (WT) protein in HEK-293 cells but also Xenopus laevis oocytes was associated with a poorly selective outwardly rectifying current in both models, resembling the one observed upon expression of the E protein [15,[20][21][22]. However, again, these observations were not replicated by other laboratories [23]. ...
... In contrast, recording whole-cell currents on roundshaped and detached cells, we observed large outwardly rectifying currents only in E or 3a protein-expressing cells but not in control dying cells. This current is reminiscent of those observed in previous publications using HEK-293 cells and oocytes expressing SARS-CoV-1 proteins [13,[20][21][22]. The application of carbenoxolone and probenecid, two inhibitors of pannexin channels, suggests for the first time that these currents are pannexin-mediated conductances, potentially activated by altered morphology or apoptosis. ...
Controversial reports have suggested that SARS-CoV E and 3a proteins are plasma membrane viroporins. Here, we aimed at better characterizing the cellular responses induced by these proteins. First, we show that expression of SARS-CoV-2 E or 3a protein in CHO cells gives rise to cells with newly acquired round shapes that detach from the Petri dish. This suggests that cell death is induced upon expression of E or 3a protein. We confirmed this by using flow cytometry. In adhering cells expressing E or 3a protein, the whole-cell currents were not different from those of the control, suggesting that E and 3a proteins are not plasma membrane viroporins. In contrast, recording the currents on detached cells uncovered outwardly rectifying currents much larger than those observed in the control. We illustrate for the first time that carbenoxolone and probenecid block these outwardly rectifying currents; thus, these currents are most probably conducted by pannexin channels that are activated by cell morphology changes and also potentially by cell death. The truncation of C-terminal PDZ binding motifs reduces the proportion of dying cells but does not prevent these outwardly rectifying currents. This suggests distinct pathways for the induction of these cellular events by the two proteins. We conclude that SARS-CoV-2 E and 3a proteins are not viroporins expressed at the plasma membrane.
... Furthermore, several secondary metabolites, such as phenolic compounds, which inhibit the activity of the SARS-3CLpro enzyme; quercetin, which inhibits the cellular entry of SARS-CoV and the activity of SARS-CoV 3Clpro; kaempferol, which inhibits the 3a ion channel of coronavirus; luteolin, which binds the surface spike protein of SARS-CoV; and apigenin and luteolin, which inhibit the activity of SARS-CoV 3CLpro, are among the secondary metabolites that exhibit antiviral action. The ability of chrysin to inhibit the production of viral capsid proteins and the replication of RNA in enterovirus 71 [36][37][38][39] is proof that chrysin also possesses antiviral properties. Among the naturally occurring chemical substances that have been demonstrated to inhibit the spike protein, PLpro, and 3CLpro of SARS-CoV-2, curcumin, kaempferol, licoleafol, myricitrin, and silybin are among the chemicals that have been identified. ...
Propolis, which continues to be a fascinating source of these chemicals, is related to several natural chemical substances that have antibacterial, antifungal, antiviral, antioxidant, and anti-inflammatory properties. These are just some of the natural chemical substances and their effects. The ever-increasing prevalence of respiratory tract infections brought on by a wide range of pathogenic viruses has led to the ongoing search for complementary methods of prevention and treatment that can be employed with medication. The characteristics of propolis could be of substantial value in preventing and treating respiratory tract illnesses caused by viruses. These viruses include severe acute respiratory syndrome coronavirus 2, influenza, parainfluenza, and rhinoviruses. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, has been one of the most significant challenges over the previous few years. In recent years, there has been a rise in research focused on the efficacy of various propolis formulations against SARS-CoV-2 as an adjuvant therapy for this infection. Several primary pathways of anti-SARS-CoV-2 action have been proven to be associated with propolis. One way is to inhibit the interaction between the S1 spike protein and the ACE-2 protein. Other mechanisms include reducing coronavirus particles and reducing viral replication through decreased RNA transcript production in cells.
... Kaempferol, a natural flavonoid, exhibits antioxidant, antiinflammatory, antimicrobial, antidiabetic, anticancer, and antiviral activities. Antiviral activity of kaempferol has been reported against human cytomegalovirus (Mitrocotsa et al., 2000), human immunodeficiency virus 1 (HIV-1) (Behbahani et al., 2014), Japanese encephalitis virus (JEV) (Care et al., 2020) and coronaviruses (Schwarz et al., 2014). In the current study, molecular docking predicted that binding occurs between kaempferol and SARS-CoV-2 6LU7 and 6Y2E proteases with high affinities of -7.6 and 5.2 kcal/mol, respectively (Table 2). ...
This study aimed to evaluate the inhibitory effects of key polyphenols and flavonoids from Syzygium aromaticum and Citrus limon, along with main organosulfur compounds from Allium sativum, against SARS-CoV-2 proteases 6LU7 and 6Y2E. The methods used included in silico molecular docking, ADMET analysis, and molecular dynamics simulations. Structures of 34 natural products found in three medicinal plants were docked to these two critical proteins. For 6LU7 protease, 24 compounds exhibited binding affinities greater than or equal to-6 Kcal/mol. While, for 6Y2E protease, 6 compounds exhibited binding affinities greater than or equal to-6 Kcal/mol. Molecules with a maximum binding affinity equal to-8.4 kcal/mol show good hydrogen bonds with the two proteases under investigation, 6LU7 and 6Y2E. The ADME properties of ellagic acid, kaempferol, and biflorin showed human oral absorption rates of 43.6%, 67.5%, and 44.8% respectively, and Caco-2 permeability values of 33.429, 163.1, and 187.9 nm/s. Blood-brain partition coefficients indicate biflorin is within the acceptable range (-3 to 1.2), while ellagic acid and kaempferol exceed acceptable values (>1.2). The molecular dynamics simulation study demonstrates the rigidity and stability of the docked complexes, evidenced by substantial energy reductions indicating system stabilization. Hesperidin binds more rapidly to 6LU7 than to 6Y2E, while diosmin displayed the quickest kinetics with 6Y2E. These compounds might be used therapeutically as complementary medicines and/or to conceptualize new drugs against COVID-19. Citation: Chebaibi, M.; Mssillou, I.; Allali, A.; Bourhia, M.; Bousta, D.; Gonçalves, R.F.B.; Hoummani, H.; Aboul-Soud, M. A. M.; Augustyniak, M.; Achour, S. Antiviral Activities of Compounds Derived from Medicinal Plants against SARS-CoV-2
... [28] In particular, kaempferol glycosides are good candidates for 3a-channel proteins of coronaviruses. [29] The ethanol extract of P. bleo fruits was predominant with 5,7-dihydroxychromone-7-β-D-glucoside. It was proposed that 5,7-dihydroxychromone is one of the active compounds that may contribute to regulate blood glucose levels. ...
... The results suggested that viral ion channels could be a good target for developing antiviral agents. The study also found that kaempferol glycosides were effective candidates for inhibiting 3a channel proteins of coronaviruses [128]. ...
Natural products and their bioactive compounds have been used for centuries to prevent and treat numerous diseases. Kaempferol, a flavonoid found in vegetables, fruits, and spices, is recognized for its various beneficial properties, including its antioxidant and anti-inflammatory potential. This molecule has been identified as a potential means of managing different pathogenesis due to its capability to manage various biological activities. Moreover, this compound has a wide range of health-promoting benefits, such as cardioprotective, neuroprotective, hepatoprotective, and anti-diabetic, and has a role in maintaining eye, skin, and respiratory system health. Furthermore, it can also inhibit tumor growth and modulate various cell-signaling pathways. In vivo and in vitro studies have demonstrated that this compound has been shown to increase efficacy when combined with other natural products or drugs. In addition, kaempferol-based nano-formulations are more effective than kaempferol treatment alone. This review aims to provide detailed information about the sources of this compound, its bioavailability, and its role in various pathogenesis. Although there is promising evidence for its ability to manage diseases, it is crucial to conduct further investigations to know its toxicity, safety aspects, and mechanism of action in health management.
... Flavonoid derivatives are thought to prevent the proteolytic activity of SARS coronavirus (SARS-CoV) 3CLpro, and in some instances, these compounds can act as antivirals by preventing SARS-CoV 3CLpro activity. [13][14][15] Herbacetin is an anti-coronavirus drug from the flavonoid family. [16,17] The results of the docking study on the homologs of herbacetin, kaempferol and morine ( Figure 2) showed that their binding modes are related to their binding affinity. ...
Flavonoids are natural products commonly found in the human diet with anti‐viral activity. The electrochemical activity of flavonoids is effective in their inhibitory properties. Herbacetin is an anti‐coronavirus drug from the flavonoid family. To understand structure‐electrochemical activity relations, ab initio calculations on some selected herbacetin derivatives were carried out using Gaussian 09 in B3LYP/6‐311G*. The effect of the position and type of the various substituents in the ring A of the flavone backbone are considered. The oxygen charge density of the hydroxyl group on C8 (O8) in the considered herbacetins was compared using nuclear quadrupole coupling constants (NQCC) calculations. Results showed that the presence of the amino group in the ortho position of O8 has the most significant effect on increasing the charge density of the O8 atom (O8‐NQCC=9.23 MHz). Based on the proposed mechanism of these drugs, ortho‐amino herbacetin is expected to show a significant anti‐coronavirus effect. Comparison of calculated O8‐NQCCs of tangeretin and nobiletin with herbacetin shows that with the replacement of OH with OCH3, the charge density of oxygen atoms decreases (about 2 MHz). Therefore tangeretin and nobiletin have a lower drug effect than herbacetin. Natural bond orbital (NBO) results are in agreement with calculated NQCCs.
... Focus on the COVID-19, some secondary metabolites such as emodin, palmatine are suggested as potential drug candidates against SARS-CoV-2 [49,50] (Table 2), [51][52][53][54]. Quercetine increased caspase activity [55], kaemferol inhibited TNF-α, IL-6, IL-1β cytokinins and increase SOD [56], resveratrol inhibited MAPK, PI3K, AKT [57], and also cannabidiol inhibited expression of TNF-α and IL-6 cytokines [58], (Fig. 2, drawn by Biorender). Particularly, these natural compounds have some roles in antiviral disease which has cancellation to penetration to the host cell (lectin), adhesion to lungs and reproduction (alkaloids) of coronavirus, as well as inhibition of binding to the surface of host cells by changing proteins in the surface of virus cells (polyphenols), prevent to replication of virus by inhibition reverse transcriptase enzyme (flavonoids and terpenes), block translation proteins and recognize viral proteins for replication, repress active caspase 1 for preventing cytokine storm [59]. ...
An arsenal of naturopathic compounds for the treatment of COVID-19: A comprehensive review
... Our yeast assay aligns with previous research identifying ORF3a as an ion channel (Kern et al., 2021;Lu et al., 2006;Schwarz et al., 2014;Schwarz et al., 2011), adding to the evidence supporting this characterization. Nonetheless, the indirect nature of our findings leaves room for alternative hypotheses. ...
ORF3a is an accessory protein expressed by all human pathogen coronaviruses and is the only accessory protein that strongly affects viral fitness. Its deletion reduces severity in both alpha- and beta-coronaviruses, demonstrating a conserved function across the superfamily. Initially regarded as a non-selective cation channel, ORF3a's function is now disputed. Here, we show that ORF3a from SARS, but not SARS-CoV-2, promotes potassium conductance in a yeast model system commonly used to study potassium channels. ORF3a-mediated potassium conductance is also sensitive to inhibitors, including emodin, carbamazepine, and nifedipine. This model may be used in future studies on ORF3a and related proteins.
... Kaempferol and its water-soluble glycoside juglanin were tested for the inhibition of barium ion (Ba 2+ )-sensitive current created by the 3a virus ion channel using xenopus oocyte with a heterologously expressed 3a protein as a model system. Juglanin, which carries an arabinose sugar, inhibited 3a-mediated current with an IC 50 value of 2.3 μM (Schwarz et al. 2014). ...
Anthropogenic factors and climate changes result in the emergence and re-emergence of infectious diseases. Viruses are one of the major causative agents of contagious diseases, and they have tremendous potential to cause pandemics and epidemics. The discovery and development of anti-viral drugs are crucial to combat viral diseases, and plant and microbial origin molecules are ideal candidates for novel anti-viral agent development. The abundant chemical diversity of natural products makes them unique resources of bioactive molecules. The unique characteristics of RNA viruses, such as error-prone replication and high host adaptability that help cause diseases in humans and animals, make them potential causative agents for future pandemics. Thus, channeling natural products for developing anti-viral agents against RNA viruses is an important strategy for pandemic preparedness. Natural product-based drug discovery has challenges. However, using modern scientific tools, an optimized natural product-based drug pipeline can overcome natural product-based drug discovery challenges to develop highly potent, greener, sustainable anti-virals. This article explores the anti-viral activities of natural products derived from microbes and plants.
... In the past decade, the anti-viral ability of kaempferol has been well investigated in human diseases. Several studies indicate that kaempferol displays potent as well as broad antiviral activity against herpesvirus (26), hepatitis virus (27), influenza virus (28), and coronavirus (29,30). However, there has been little research on the anti-viral effects of kaempferol in aquaculture. ...
Channel catfish virus (CCV, Ictalurid herpesvirus 1) is the causative pathogen of channel catfish virus disease, which has caused high mortality and substantial economic losses in the catfish aquaculture industry. Due to the lack of licensed prophylactic vaccines and therapeutic drugs, the prevention and control of CCV infection seem to remain stagnant. Active compounds from medicinal plants offer eligible sources of pharmaceuticals and lead drugs to fight against endemic and pandemic diseases and exhibit excellent effect against viral infection. In this study, we evaluated the antiviral ability of 12 natural compounds against CCV with cell models in vitro and found kaempferol exhibited the strongest inhibitory compound against CCV infection among all the tested compounds. Correspondingly, kaempferol decreased transcription levels of viral genes and the synthesis of viral proteins, as well as reduced proliferation and release of viral progeny, the severity of the CPE induced by CCV in a dose-dependent manner, based on quantitative real-time PCR (RT-qPCR), western blotting, viral cytopathic effects (CPE) and viral titer assessment. Moreover, time-of-drug-addition assays, virus attachment, and penetration assays revealed that kaempferol exerted anti-CCV activity probably by blocking attachment and internalization of the viral entry process. Altogether, the present results indicated that kaempferol may be a promising candidate antiviral agent against CCV infection, which shed light on the development of a novel and potent treatment for fish herpesvirus infection.
... Some other components having great inhibitory potential against SARS-CoV-2 are demonstrated in Table 7. Table 7. Chemical constituents of S. nigrum that showed inhibitory potential against SARS-CoV-2 (Khalil and Tazeddinova 2020; Schwarz et al., 2014). ...
Three-fourths of the world’s population uses 30% of all plant species as a safe source of disease control and treatment. Similarly, Solanum nigrum (Black nightshade), a therapeutic herb with small, spherical berry fruits, is used as an herbal remedy to treat many different diseases, including respiratory diseases. According to recent research, this plant can aid in the management of COVID-19. Alkaloids, flavonoids, steroids, glycoproteins, tannins, polysaccharides, polyphenolic compounds etc. are found in this plant. Among them, polyphenolic compounds are mostly responsible for showing various pharmacological activity. Anti-tumor, antioxidant, anti-diabetic, anti-inflammatory, anti-seizure, immunostimulant, hepatoprotective, antimicrobial activities are shown by S. nigrum according to multiple studies. The aim of this article is to compile different aspect of this plant like plant description, uses, chemical constituents, pharmacological activities and especially its role in the management of COVID-19 and probable mechanism behind this role. J. Asiat. Soc. Bangladesh, Sci. 49(2): 237-263, December 2023
... Furthermore, a computational study exhibited the activity of its bioactive compounds (kaempferol, kaempferol glycosides, and acylated kaempferol glucoside derivatives) to block the 3a channel protein of SARS-CoV. Inhibition of this channel would inactivate virus production and allow the host to build up its immunity system (Schwarz et al. 2014). Another docking investigation indicated that kaempferol, due to its hydroxyl, ketone, and ether groups, was a stronger C19M pro inhibitor than other tested natural compounds (Khaerunnisa et al. 2020). ...
Before the availability of a vaccine, Indonesian population relied on traditional medicines to prevent COVID-19. Any species used by indigenous people could lead to further investigations in modern pharmacology, to preserve ancient knowledge, and to plan for plants' conservation. The study aimed to discover and record species, methods of preparation, route of administration, and motivation in using medicinal plants by the Indonesian population during the COVID-19 pandemic. Participants of survey were selected from the people who live in Java and Bali for responding to an online structured questionnaire. Relative Frequency of Citation (RFC) was employed in the quantitative analysis of the collected data. The pharmacological relevance of the five plants with the highest RFC was further reviewed. The results showed that respondents used 59 plants from 28 families. Five species with the highest RFC were Curcuma longa (0.707), Zingiber officinale (0.674), Cymbopogon citratus (0.269), Kaempferia galanga (0.174), and Curcuma zanthorrhiza (0.165). Most plants were prepared by boiling (77.97%) and administered orally as a single ingredient or mixed with other herbals. Respondents believed that the plants were beneficial as immune-booster (71.26%), maintain good health (24.85%) and stamina (12.28%), and prevent viral infection, including COVID-19 (5.39%). The most commonly used plants might be scientifically based to boost immunity. However, their usage against COVID-19 and the medicinal value of herbal mixtures should be further investigated.
... Emodin and kaempferol derivatives have been previously shown to be inhibitors of SARS-CoV Orf3a ion channel activity [99,100]. To explore the binding mode of these natural compounds in the top-ranking SARS-CoV-2 Orf3a pocket identified by PrankWeb, molecular docking was performed. ...
Antiviral drugs are important for the coronavirus disease 2019 (COVID-19) response, as vaccines and antibodies may have reduced efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Antiviral drugs that have been made available for use, albeit with questionable efficacy, include remdesivir (Veklury®), nirmatrelvir-ritonavir (Paxlovid™), and molnupiravir (Lagevrio®). To expand the options available for COVID-19 and prepare for future pandemics, there is a need to investigate new uses for existing drugs and design novel compounds. To support these efforts, we have created a comprehensive library of 750 molecules that have been sourced from in vitro, in vivo, and in silico studies. It is publicly available at our dedicated website (https://epimedlab.org/crl/). The EpiMed Coronabank Chemical Collection consists of compounds that have been divided into 10 main classes based on antiviral properties, as well as the potential to be used for the management, prevention, or treatment of COVID-19 related complications. A detailed description of each compound is provided, along with the molecular formula, canonical SMILES, and U.S. Food and Drug Administration approval status. The chemical structures have been obtained and are available for download. Moreover, the pharmacokinetic properties of the ligands have been characterised. To demonstrate an application of the EpiMed Coronabank Chemical Collection, molecular docking was used to evaluate the binding characteristics of ligands against SARS-CoV-2 nonstructural and accessory proteins. Overall, our database can be used to aid the drug repositioning process, and for gaining further insight into the molecular mechanisms of action of potential compounds of interest.
... Among the subtypes of phytochemicals with demonstrated health effects relating to SARS-CoV-2 are polyphenols and carotenoids [80]. Several polyphenols have demonstrated anti-coronavirus activity in vitro, including quecertin and reservatrol, among others [81][82][83]. Hesperidin, another polyphenol, has demonstrated a blockade of SARS binding to angiotensin-converting enzyme-2 (ACE2) receptors [84]. Alkaloids, another group of phytochemicals have also demonstrated direct antiviral activity and RNA-dependent RNA polymerase activity [85,86]. ...
The novel coronavirus disease-2019 (COVID-19) has created a major public health crisis. Various dietary factors may enhance immunological activity against COVID-19 and serve as a method to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The dietary factors that are responsible for boosting immunity may provide a therapeutic advantage in patients with COVID-19. Investigators have demonstrated that vitamins B6, B12, C, D, E, and K, and trace elements like zinc, copper, selenium, and iron may serve as important tools for immunomodulation. Herein this is a review the peer-reviewed literature pertaining to dietary immunomodulation strategies against COVID-19. This review is intended to better define the evidence that dietary modifications and supplementation could positively influence the proinflammatory state in patients with COVID-19 and improve clinical outcomes. With appropriate insight, therapeutic interventions are discussed and directed to potentially modulate host immunity to mitigate the disease mechanisms of COVID-19.
... Some traditional herbs were also active against the infection of SARS-CoV-2 and SARS-CoV. These were blocking the ability of ACE2-host receptor to avoid the spreading of infection (Fig. 4), and derivatives of kaempferoljuglanin may also avoid the virus release from the infected cell as these can break down the 3a receptor (Letko et al., 2020;Schwarz et al., 2014). It was also investigated that different polyphenols are active in reducing the enzymatic activity of SARS-3CLpro, such as extracts of litchi seeds, rhubarb, Houttuynia cordata, and Isatis indigotica roots (Singh et al., 2022). ...
... Some traditional herbs were also active against the infection of SARS-CoV-2 and SARS-CoV. These were blocking the ability of ACE2 host receptor to avoid the spreading of infection, and derivatives of kaempferol-juglanin may also avoid the virus release from the infected cell as these can break down the 3a receptor (Letko et al. 2020, Schwarz et al. 2014. ...
The increasing prevalence of viral infections and the emergence of drug-resistant or mutant strains necessitate the exploration of novel antiviral strategies. Accumulating evidence suggests that natural plant products have significant potential to enhance the human antiviral response. Various plant natural products (PNPs) known for their antiviral properties have been evaluated for their ability to modulate immune responses and inhibit viral infections. Research has focused on understanding the mechanisms by which these PNPs interact with the human immune system and their potential to complement existing antiviral therapies. PNPs control compounds such as alkaloids, flavonoids, terpenoids, and polyphenols to promote antiviral cytokine synthesis, increase T-cell and macrophage activity, and activate antiviral genes. Studies have investigated the molecular interactions between PNPs, viruses, and host cells, exploring the potential of combining PNPs with conventional antiviral drugs to enhance efficacy. However, several challenges remain, including identifying, characterizing, and standardizing PNP extracts, optimizing dosages, improving bioavailability, assessing long-term safety, and navigating regulatory approval. The promising potential of PNPs is being explored to develop new, effective, and natural antiviral therapies. This review outlines a framework for an integrative approach to connect the full potential of PNPs in combating viral infections and improving human health. By combining natural plant products with conventional antiviral treatments, more effective and sustainable management of viral diseases can be achieved.
Aims
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been linked to cardiovascular complications, notably cardiac arrhythmias. The open reading frame (ORF) 3a of the coronavirus genome encodes for a transmembrane protein that can function as an ion channel. The aim of this study was to investigate the role of the SARS-CoV-2 ORF 3a protein in COVID-19-associated arrhythmias and its potential as a pharmacological target.
Methods and results
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and cultured human fibroblasts were infected with SARS-CoV-2. Subsequent immunoblotting assays revealed the expression of ORF 3a protein in hiPSC-CM but not in fibroblasts. After intracytoplasmic injection of RNA encoding ORF 3a proteins into Xenopus laevis oocytes, macroscopic outward currents could be measured. While class I, II, and IV antiarrhythmic drugs showed minor effects on ORF 3a-mediated currents, a robust inhibition was detected after application of class III antiarrhythmics. The strongest effects were observed with dofetilide and amiodarone. Finally, molecular docking simulations and mutagenesis studies identified key amino acid residues involved in drug binding.
Conclusion
Class III antiarrhythmic drugs are potential inhibitors of ORF 3a-mediated currents, offering new options for the treatment of COVID-19-related cardiac complications.
Juglanin (kaempferol 3-O-α-L-arabinofuranoside) is a flavonol glycoside occurring in many plants, including its commercial sources Juglans regia, Polygonum aviculare and Selliguea hastata. Recent extensive studies have explored the potential of using juglanin in various pathological conditions, including cardiovascular disorders, central nervous and skeletal system disorders, metabolic syndrome, hepatic injury, and cancers. The results indicated a wide range of effects, like anti-inflammatory, anti-oxidant, anti-fibrotic, anti-thrombotic, anti-angiogenic, hepatoprotective, hypolipidemic, hypoglycemic, anti-apoptotic (normal cells), and pro-apoptotic (cancer cells). The health-promoting properties of juglanin can be attributed to its influence on many signaling pathways, associated with SIRT1, AMPK, Nrf2, STING, TLR4, MAPKs, NF-κB, AKT, JAK, and their downstream genes. This review primarily summarizes the current knowledge of molecular mechanisms, pharmacokinetics, biocompatibility, and human use safety of juglanin. In addition, the most promising new plant sources and other existing challenges and prospects have also been reviewed and discussed, aiming to provide direction and rationale for the further development and broader pharmaceutical application of juglanin.
Viroporins possess important potential as antiviral targets due to their critical roles during virus life cycles, spanning from virus entry to egress. Although the antiviral amantadine targets the M2 viroporin of influenza A virus, successful progression of other viroporin inhibitors into clinical use remains challenging. These challenges relate in varying proportions to a lack of reliable full‐length 3D‐structures, difficulties in functionally characterising individual viroporins, and absence of verifiable direct binding between inhibitor and viroporin. This review offers perspectives to help overcome these challenges. We provide a comprehensive overview of the viroporin family, including their structural and functional features, highlighting the moldability of their energy landscapes and actions. To advance the field, we suggest a list of best practices to aspire towards unambiguous viroporin identification and characterisation, along with considerations of potential pitfalls. Finally, we present current and future scenarios of, and prospects for, viroporin targeting drugs.
Aims
The aim of the present review was to highlight natural product investigations in silico and in vitro to find plants and chemicals that inhibit or stimulate angiotensin-converting enzyme 2 (ACE-2).
Background
The global reduction of incidents and fatalities attributable to infections with SARS-CoV-2 is one of the most public health problems. In the absence of specific therapy for coronavirus disease 2019 (COVID-19), phytocompounds generated from plant extracts may be a promising strategy worth further investigation, motivating researchers to evaluate the safety and anti-SARS-CoV-2 effectiveness of these ingredients.
Objective
To review phytochemicals in silico for anti-SARS-CoV-2 activity and to assess their safety and effectiveness in vitro and in vivo.
Methods
The present review was conducted using various scientific databases and studies on anti-SARS-CoV-2 phytochemicals were analyzed and summarized. The results obtained from the in silico screening were subjected to extraction, isolation, and purification. The in vitro studies on anti-SarcoV-2 were also included in this review. In addition, the results of this research were interpreted, analyzed, and documented on the basis of the bibliographic information obtained.
Results
This review discusses recent research on using natural remedies to cure or prevent COVID-19 infection. The literature analysis shows that the various herbal preparations (extracts) and purified compounds can block the replication or entrance of the virus directly to carry out their anti-SARS-CoV-2 effects. It is interesting to note that certain items can prevent SARS-CoV-2 from infecting human cells by blocking the ACE-2 receptor or the serine protease TMPRRS2. Moreover, natural substances have been demonstrated to block proteins involved in the SARS-CoV-2 life cycle, such as papain- or chymotrypsin-like proteases.
Conclusion
The natural products may have the potential for use singly or in combination as alternative drugs to treat/prevent COVID-19 infection, including blocking or stimulating ACE-2. In addition, their structures may provide indications for the development of anti-SARS-CoV-2 drugs.
ABSTRACT
Chalcones with a C6-C3-C6 backbone are a class of plant-derived polyphenolic metabolites structurally related to flavonoids, of which two phenyl rings are connected via an α- and β-unsaturated carbonyl chain. Indeed, these secondary metabolites are precursors of flavonoids, as they are readily converted to the corresponding flavanones by the action of chalcone isomerase. Chalcones are found in various plant resources and possess a myriad of biological/pharmacological activities, including antioxidant, anticancer, antiviral, anti-inflammatory, and immunomodulatory effects. Given the outbreak of harmful viral diseases like Ebola, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Mother Nature has been recognized as the most beneficial choice to look for potential candidates to target the variety of human viruses. So, the leaves of an Indian medicinal plant containing chalcones inhibited in vitro SARS-CoV-2 replication by blocking viral entry into host cells with high safety and low toxicity. Various researchers have also computationally studied the potency of chalcones as antiviral drugs toward SARS-CoV-2, the virus that caused COVID-19. As previously reported, prenylated chalcones (i.e., xanthoangelols B, D, E, and F) derived from Angelica keiskei inhibited in vitro the key SARS-CoV enzymes, including 3CLpro (chemotrypsin-like protease) and PLpro (papain-like protease), with IC50 ranges of 1.2‒34.1 μM. Another in vitro study reported that synthetic chalcones, for example, a new ciprofloxacin-chalcone hybrid, can dose-dependently inhibit SARS-CoV-2 3CLpro in Vero cells (IC50 value of 0.6 μM). Although chalcones may provide excellent anti-SARS-CoV-2 compounds, further research is required to investigate their efficiency and safety in clinical trials.
This chapter will cover the current knowledge on chalcones and, in some cases, their synthetic derivatives against SARS-CoV-2. Furthermore, the inhibition of different enzymes, which are related to different stages of viral replication and progression of COVID-19, will be discussed.
Porcine epidemic diarrhea virus (PEDV) has caused severe damage to the global pig industry in the past 20 years, creating an urgent demand for the development of associated medications. Flavonoids have emerged as promising candidates for combating coronaviruses. It is believed that certain flavonoids can directly inhibit the 3C-like protease (3CLpro), thus displaying antiviral activity against coronaviruses. In this investigation, we applied a flavonoid library to screen for natural compounds against PEDV 3CLpro. Baicalein and baicalin were found to efficiently inhibit PEDV 3CLproin vitro, with the IC50 value of 9.50 ± 1.02 μM and 65.80 ± 6.57 μM, respectively. A docking analysis supported that baicalein and baicalin might bind to the active site and binding pocket of PEDV 3CLpro. Moreover, both baicalein and baicalin successfully suppressed PEDV replication in Vero and LLC-PK1 cells, as indicated by reductions in viral RNA, protein, and titer. Further investigation revealed that baicalein and baicalin mainly inhibited the early viral replication of the post-entry stage. Furthermore, baicalein showed potential effects on the attachment or invasion step of PEDV. Collectively, our findings provide experimental proof for the inhibitory effects of baicalein and baicalin on PEDV 3CLpro activity and PEDV infection. These discoveries may introduce novel therapeutic strategies for controlling porcine epidemic diarrhea (PED).
The COVID-19 pandemic that started in 2019 and resulted in significant morbidity and mortality continues to be a significant global health challenge, characterized by inflammation, oxidative stress, and immune system dysfunction.. Developing therapies for preventing or treating COVID-19 remains an important goal for pharmacology and drug development research. Polyphenols are effective against various viral infections and can be extracted and isolated from plants without losing their therapeutic potential. Researchers have developed methods for separating and isolating polyphenols from complex matrices. Polyphenols are effective in treating common viral infections, including COVID-19, and can also boost immunity. Polyphenolic-based antiviral medications can mitigate SARS-CoV-2 enzymes vital to virus replication and infection. Individual polyphenolic triterpenoids, flavonoids, anthraquinonoids, and tannins may also inhibit the SARS-CoV-2 protease. Polyphenol pharmacophore structures identified to date can explain their action and lead to the design of novel anti-COVID-19 compounds. Polyphenol-containing mixtures offer the advantages of a well-recognized safety profile with few known severe side effects. However, studies to date are limited, and further animal studies and randomized controlled trials are needed in future studies. The purpose of this study was to review and present the latest findings on the therapeutic impact of plant-derived polyphenols on COVID-19 infection and its complications. Exploring alternative approaches to traditional therapies could aid in developing novel drugs and remedies against coronavirus infection.
Efforts have been made during the past two years to find out novel and effective drugs against SARS-CoV-2. Plants have become a source for the development of novel and improved medications against viruses due to the advancement of biomedical technologies and pharmacological evaluations. Phytocompounds including flavonoids, phenolics, alkaloids, lignans, terpenoids and tannins have been demonstrated to have antiviral properties, particularly against SARS CoV-2. The present review discusses information on the potential antiviral traditional medicines, medicinally important plants, their extracts and the specific bioactive compounds present in such plants along with their mode of action. It also gives an insight regarding the limitations in exploring medicinal plants for phytocompound antimicrobial drug discovery, and suggests novel and prospective strategies considering the fact that they are naturally occurring and relatively less harmful with a view to combating the present pandemic and the ones that may happen in the future.
COVID-19 has been a major global health concern for the past three years, and currently we are still experiencing coronavirus patients in the following years. The virus, known as SARS-CoV-2, shares a similar genomic identity with previous viruses such as SARS-CoV and MERS-CoV. To combat the pandemic, modern drugs discovery techniques such as in silico experiments for docking and virtual screening have been employed to design new drugs against COVID-19. However, the release of new drugs for human use requires two safety assessment steps consisting of preclinical and clinical trials. To bypass these steps, scientists are exploring the potential of repurposing existing drugs for COVID-19 treatment. This approach involves evaluating antiviral activity of drugs previously used for treating respiratory diseases against other enveloped viruses such as HPV, HSV, and HIV. The aim of this study is to review repurposing of existing drugs, traditional medicines, and active secondary metabolites from plant-based natural products that target specific protein enzymes related to SARS-CoV-2. The review also analyzes the chemical structure and activity relationship between selected active molecules, particularly flavonol groups, as ligands and proteins or active sites of SARS-CoV-2.
This study aimed to evaluate in vivo the use of the extract from the leaves of Melia azedarach in the ethyl acetate fraction at a concentration of 150 µg/mL as an antiretroviral treatment against small ruminant lentiviruses (SRLV) in goat colostrum, and milk with a 90-min action. Two groups of six kids were treated with the extract. One group received three supplies of colostrum from does naturally positive for SRLV, treated with the ethyl acetate fraction of M. azedarach (EAF-MA) for three days, while the other group consumed milk from does also carrying the virus with the respective extract twice a day for five days. After undergoing treatment, all animals began to receive thermized milk until weaning (60 days) and were monitored for six months using nested polymerase chain reaction (nPCR) and western blot (WB) tests. The study revealed cumulative percentages of positive animals in WB or nPCR in the milk group of 66.66% on the seventh day, 83.33% in the following week, and 100% at 120 days, while the colostrum group showed values of 66.66% at 14 days, 83.33% at 90 days, and 100% at 120 days. Variation and intermittency were observed in viral detection, but all animals tested positive in WB or nPCR at some point. A potential delay in infection was observed, which was more significant in the colostrum group. The need for the combination of serological and molecular tests for a more efficient detection of the disease is also emphasized.
In early 2020, a global pandemic was announced due to the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known to cause COVID-19. Despite worldwide efforts, there are only limited options regarding antiviral drug treatments for COVID-19. Although the vaccines are now available, issues such as declining efficacy against different SARS-CoV-2 variants and aging of vaccine-induced immunity highlight the importance of finding more antiviral drugs as a second line of defense against the disease. Drug repurposing has been used to rapidly find COVID-19 therapeutic options. Due to the lack of clinical evidence for the therapeutic benefits and certain serious side effects of repurposed antivirals, the search for an antiviral drug against SARS-CoV-2 with fewer side effects continues. In recent years, numerous studies have included antiviral chemicals from a variety of plant species. A better knowledge of the possible antiviral natural products and their mechanism against SARS-CoV-2 will help to develop stronger and more targeted direct-acting antiviral agents. The aim of the present study was to compile the current data on potential plant metabolites that can be investigated in COVID-19 drug discovery and development. This review represents a collection of plant secondary metabolites and their mode of action against SARS-CoV and SARS-CoV-2.
Kaempferol and its derivatives are flavonoids found in various plants, and a considerable number of these have been used in various medical applications worldwide. Kaempferol and its compounds have well-known antioxidant, anti-inflammatory and antimicrobial properties among other health benefits. However, the antiviral properties of kaempferol are notable, and there is a significant number of experimental studies on this topic. Kaempferol compounds were effective against DNA viruses such as hepatitis B virus, viruses of the alphaherpesvirinae family, African swine fever virus, and pseudorabies virus; they were also effective against RNA viruses, namely feline SARS coronavirus, dengue fever virus, Japanese encephalitis virus, influenza virus, enterovirus 71, poliovirus, respiratory syncytial virus, human immunodeficiency virus, calicivirus, and chikungunya virus. On the other hand, no effectiveness against murine norovirus and hepatitis A virus could be determined. The antiviral action mechanisms of kaempferol compounds are various, such as the inhibition of viral polymerases and of viral attachment and entry into host cells. Future research should be focused on further elucidating the antiviral properties of kaempferol compounds from different plants and assessing their potential use to complement the action of antiviral drugs.
In the present era of the COVID-19 pandemic, viral infections remain a major cause of morbidity and mortality worldwide. In this day and age, viral infections are rampant and spreading rapidly. Among the most aggressive viral infections are ebola, AIDS (acquired immunodeficiency syndrome), influenza, and SARS (severe acute respiratory syndrome). Even though there are few treatment options for viral diseases, most of the antiviral therapies are ineffective owing to frequent mutations, the development of more aggressive strains, drug resistance, and possible side effects. Traditionally, herbal remedies have been used by healers, including for dietary and medicinal purposes. Many clinical and scientific studies have demonstrated the therapeutic potential of plant-derived natural compounds. Because of unsafe practices like blood transfusions and organ transplants from infected patients, medical supply contamination. Our antiviral therapies cannot achieve sterile immunity, and we have yet to find a cure for these pernicious infections. Herbs have been shown to improve therapeutic efficacy against a wide variety of viral diseases because of their high concentration of immunomodulatory phytochemicals (both immunoinhibitory and anti-inflammatory). Combined with biotechnology, this folk medicine system can lead to the development of novel antiviral drugs and therapies. In this Review, we will summarize some selected bioactive compounds with probable mechanisms of their antiviral actions, focusing on the immunological axis of these compounds.
Coronavirus disease 2019 (COVID-19) and malaria are two different diseases but both lead to serious crisis in public health in Africa. These two distinct diseases are caused by different pathogens, i.e., viruses and parasites, respectively. However, interestingly, they share some similarities in the symptomatic manifestation. In the past years, a number of studies have been conducted in Africa for proposing medicinal plants that have potential roles in COVID-19 management. Among them, some have a strong correlation with those that have been used against malaria when compared. The most cited botanical families against both diseases are mainly from the Pentapetalae group. For combating malaria, different species of the Artemisia genus have been proposed. One of the most critical bioactive compounds, i.e., artemisinin and its derivatives is evaluated in bioassays and then clinical trials for proving its efficacy. Additionally, some secondary metabolites from these plants have shown potential effects against coronavirus, but the mode of action remains to be elucidated in the future.KeywordsCOVID-19SARS-CoV-2AfricaMedicinal plantsMalaria
SARS-CoV-2 is a virus belonging to the species “severe acute respiratory syndrome-related coronavirus” (SARSr-CoV), a strain that causes the respiratory sickness driving the continuing coronavirus disease 2019 (COVID-19) pandemic, and a descendant of the SARS-CoV-1 virus, which caused the SARS epidemic in 2002–2004. Since the outbreak of the pandemic, researchers have sought antivirals. India’s prominence as a center for Ayurvedic and medicinal plants makes evaluating plant-derived bioactive compounds for their applicability and efficacy as long-term antiviral treatments all the more pertinent, given that newly produced vaccines continue to raise issues. In the present day, the drug discovery process is intrinsically leaning toward in silico methodologies because computational procedures can be pretty diverse, requiring interdisciplinary studies. Besides, the in silico application appears judiciously effective and commercially viable for identifying effective molecules against specific diseases. Consequently, numerous promising in silico experiments using plant-derived bioactive compounds against SARS-CoV-2 have been conducted. The SARS-CoV-2 major protease is regarded as one of the best therapeutic targets because it plays a crucial role in recognizing CoV-encoded polyproteins that aid in the formation of replication and transcription machinery. Diverse groups of plant bioactive substances have been discovered from sources such as mangosteen, mushrooms, tea, and other medicinal foundations through molecular docking and molecular dynamics, multi-omics, systems studies, and different in silico methods leading to suppression, preventing viral replication and infection by blocking viral proteins such as 3-chymotrypsin-like cysteine protease (3CLpro) and papain-like protease 2 (PLpro) and other mechanisms. This chapter focuses on the techniques used for in silico studies to identify many bioactive phytochemicals and their efficacy against SARS-CoV-2.KeywordsSARS-CoV-2Plant-derived bioactive compoundsMolecular dockingIn silico drug developmentDrug target
Humans, in most cultures, have been using natural substances as a primary source of medicine until the discovery of modern medicine in the nineteenth century. With developments in chemistry, it became possible to closely examine plant materials and identify biologically active constituents to understand their mechanisms of action. In 1804, Sertürner purified morphine from Papaver somniferum and found that it produced the opium’s analgesic and sedative effects. He called the isolated alkaloid “morphism” after the Greek god of dreams, Morpheus. His success led others to seek the active principles of plants. A few years later, quinine was purified from Cinchona and cocaine from Erythroxylum coca. Those have been the most fruitful approach for validating ancient cultures’ use of plants for medicine.
Mosquitoes are the primary vector for West Nile virus, a flavivirus. The virus’s ability to infiltrate and establish itself in increasing numbers of nations has made it a persistent threat to public health worldwide. Despite the widespread occurrence of this potentially fatal disease, no effective treatment options are currently on the market. As a result, there is an immediate need for the research and development of novel pharmaceuticals. To begin, molecular docking was performed on two possible West Nile virus target proteins using a panel of twelve natural chemicals, including Apigenin, Resveratrol, Hesperetin, Fungisterol, Lucidone, Ganoderic acid, Curcumin, Kaempferol, Cholic acid, Chlorogenic acid, Pinocembrin, and Sanguinarine. West Nile virus methyltransferase (PDB ID: 2OY0) binding affinities varied from −7.4 to −8.3 kcal/mol, whereas West Nile virus envelope glycoprotein affinities ranged from −6.2 to −8.1 kcal/mol (PDB ID: 2I69). Second, substances with larger molecular weights are less likely to be unhappy with the Lipinski rule. Hence, additional research was carried out without regard to molecular weight. In addition, compounds 01, 02, 03, 05, 06, 07, 08, 09, 10 and 11 are more soluble in water than compound 04 is. Besides, based on maximum binding affinity, best three compounds (Apigenin, Curcumin, and Ganoderic Acid) has been carried out molecular dynamic simulation (MDs) at 100 ns to determine their stability. The MDs data is also reported that these mentioned molecules are highly stable. Finally, advanced principal component analysis (PCA), dynamics cross-correlation matrices (DCCM) analysis, binding free energy and dynamic cross correlation matrix (DCCM) theoretical study is also included to established mentioned phytochemical as a potential drug candidate. Research has indicated that the aforementioned natural substances may be an effective tool in the battle against the dangerous West Nile virus. This study aims to locate a bioactive natural component that might be used as a pharmaceutical.
Background:
The continuous evolution of SARS-CoV-2 has underscored the development of broad-spectrum prophylaxis. Antivirals targeting the membrane fusion process represent promising paradigms. Kaempferol (Kae), an ubiquitous plant flavonol, has been shown efficacy against various enveloped viruses. However, its potential in anti-SARS-CoV-2 invasion remains obscure.
Purpose:
To evaluate capabilities and mechanisms of Kae in preventing SARS-CoV-2 invasion.
Methods:
To avoid interference of viral replication, virus-like particles (VLPs) constructed with luciferase reporter were applied. To investigate the antiviral potency of Kae, human induced pluripotent stem cells (hiPSC)-derived alveolar epithelial cells type II (AECII) and human ACE2 (hACE2) transgenic mice were utilized as in vitro and in vivo models, respectively. Using dual split protein (DSP) assays, inhibitory activities of Kae in viral fusion were determined in Alpha, Delta and Omicron variants of SARS-CoV-2, as well as in SARS-CoV and MERS-CoV. To further reveal molecular determinants of Kae in restricting viral fusion, synthetic peptides corresponding to the conserved heptad repeat (HR) 1 and 2, involved in viral fusion, and the mutant form of HR2 were explored by circular dichroism and native polyacrylamide gel electrophoresis.
Results:
Kae inhibited SARS-CoV-2 invasion both in vitro and in vivo, which was mainly attributed to its suppressive effects on viral fusion, but not endocytosis, two pathways that mediate viral invasion. In accordance with the proposed model of anti-fusion prophylaxis, Kae functioned as a pan-inhibitor of viral fusion, including three emerged highly pathogenic coronaviruses, and the currently circulating Omicron BQ.1.1 and XBB.1 variants of SARS-CoV-2. Consistent with the typical target of viral fusion inhibitors, Kae interacted with HR regions of SARS-CoV-2 S2 subunits. Distinct from previous inhibitory fusion peptides which prevent the formation of six-helix bundle (6-HB) by competitively interacting with HRs, Kae deformed HR1 and directly reacted with lysine residues within HR2 region, the latter of which was considered critical for the preservation of stabilized S2 during SARS-CoV-2 invasion.
Conclusions:
Kae prevents SARS-CoV-2 infection by blocking membrane fusion and possesses a broad-spectrum anti-fusion ability. These findings provide valuable insights into potential benefits of Kae-containing botanical products as a complementary prophylaxis, especially during the waves of breakthrough infections and re-infections.
Flavonoids are vital candidates to fight against a wide range of pathogenic microbial infections. Due to their therapeutic potential, many flavonoids from the herbs of traditional medicine systems are now being evaluated as lead compounds to develop potential antimicrobial hits. The emergence of SARS-CoV-2 caused one of the deadliest pandemics that has ever been known to mankind. To date, more than 600 million confirmed cases of SARS-CoV2 infection have been reported worldwide. Situations are worse due to the unavailability of therapeutics to combat the viral disease. Thus, there is an urgent need to develop drugs against SARS-CoV2 and its emerging variants. Here, we have carried out a detailed mechanistic analysis of the antiviral efficacy of flavonoids in terms of their potential targets and structural feature required for exerting their antiviral activity. A catalog of various promising flavonoid compounds has been shown to elicit inhibitory effects against SARS-CoV and MERS-CoV proteases. However, they act in the high-micromolar regime. Thus a proper lead-optimization against the various proteases of SARS-CoV2 can lead to high-affinity SARS-CoV2 protease inhibitors. To enable lead optimization, a quantitative structure-activity relationship (QSAR) analysis has been developed for the flavonoids that have shown antiviral activity against viral proteases of SARS-CoV and MERS-CoV. High sequence similarities between coronavirus proteases enable the applicability of the developed QSAR to SARS-CoV2 proteases inhibitor screening. The detailed mechanistic analysis of the antiviral flavonoids and the developed QSAR models is a step forward toward the development of flavonoid-based therapeutics or supplements to fight against COVID-19.
A variety of viruses encode for proteins that can form ion channels in the membrane of infected cells. For example, the protein coded by the open-reading-frame 3a of SARS coronavirus (SARS-CoV) has been demonstrated to form a cation-selective channel that may become expressed in the infected cell, and its activation is then involved in virus release. Chinese herbal drugs that inhibit the ion channel formed by the 3a protein can be expected to inhibit virus release, and therefore they are a source for the development of novel therapeutic agents. Various drugs found in Chinese herbs are well known as anticancer agents and also have antiviral potency. In one study we tested some of them with respect to their potency to block the 3a channel. Application of the anthraquinone emodin was used as adjunct therapy in treatment of SARS, and we have demonstrated that it can inhibit the 3a ion channel as well as virus release with a K1/2 value of approximately 20 μM. Also the flavonols kaempferole and kaempferole glycosides may be potent inhibitors of the 3a channels. On the other hand, the favonol quercitin seems not to be effective. In addition, the flavanon naringenin and the isoflavon genistein were ineffective in inhibiting 3a-mediated currents. Antiviral activity of the artemisinin derivative artesunate is well documented, but we did not detect any inhibition of 3a-mediated currents. We suggest that viral ion channels, in general, may be good targets for the development of antiviral agents, and that, in particular, emodin and kaempferol gycosides are good candidates for 3a channel proteins in coronaviruses.
Flavonoids are a group of phytochemicals that have shown numerous health effects and have therefore been studied extensively. Of the six common food flavonoid classes, flavonols are distributed ubiquitously among different plant foods whereas appreciable amounts of isoflavones are found in leguminous plant-based foods. Flavonoids have shown promising health promoting effects in human cell culture, experimental animal and human clinical studies. They have shown antioxidant, hypocholesterolemic, anti-inflammatory effects as well as ability to modulate cell signaling and gene expression related disease development. Low bioavailability of flavonoids has been a concern as it can limit or even hinder their health effects. Therefore, attempts to improve their bioavailability in order to improve the efficacy of flavonoids are being studied. Further investigations on bioavailability are warranted as it is a determining factor for flavonoid biological activity.
In recent years, a number of natural products isolated from Chinese herbs have been found to inhibit proliferation, induce apoptosis, suppress angiogenesis, retard metastasis and enhance chemotherapy, exhibiting anti-cancer potential both in vitro and in vivo. This article summarizes recent advances in in vitro and in
vivo research on the anti-cancer effects and related mechanisms of some promising natural products. These natural products are also reviewed for their therapeutic potentials, including flavonoids (gambogic acid, curcumin, wogonin and silibinin), alkaloids (berberine), terpenes (artemisinin, β-elemene, oridonin, triptolide, and ursolic acid), quinones (shikonin and emodin) and saponins (ginsenoside Rg3), which are isolated from Chinese medicinal herbs. In particular, the discovery of the new use of artemisinin derivatives as excellent anti-cancer drugs is also reviewed.
Cell death and differentiation is a monthly research journal focused on the exciting field of programmed cell death and apoptosis. It provides a single accessible source of information for both scientists and clinicians, keeping them up-to-date with advances in the field. It encompasses programmed cell death, cell death induced by toxic agents, differentiation and the interrelation of these with cell proliferation.
The open-reading-frame 3a of SARS coronavirus (SARS-CoV) had been demonstrated previously to form a cation-selective channel that may become expressed in the infected cell and is then involved in virus release. Drugs that inhibit the ion channel formed by the 3a protein can be expected to inhibit virus release, and would be a source for the development of novel therapeutic agents. Here we demonstrate that emodin can inhibit the 3a ion channel of coronavirus SARS-CoV and HCoV-OC43 as well as virus release from HCoV-OC43 with a K1/2 value of about 20 μM. We suggest that viral ion channels, in general, may be a good target for the development of antiviral agents.
Ion channels are membrane proteins that are found in a number of viruses and which are of crucial physiological importance in the viral life cycle. They have one common feature in that their action mode involves a change of electrochemical or proton gradient across the bilayer lipid membrane which modulates viral or cellular activity. We will discuss a group of viral channel proteins that belong to the viroproin family, and which participate in a number of viral functions including promoting the release of viral particles from cells. Blocking these channel-forming proteins may be "lethal", which can be a suitable and potential therapeutic strategy. In this review we discuss seven ion channels of viruses which can lead serious infections in human beings: M2 of influenza A, NB and BM2 of influenza B, CM2 of influenza C, Vpu of HIV-1, p7 of HCV and 2B of picornaviruses.
To unravel mechanisms of action of dietary flavonoids in their potential role in disease prevention, it is crucial to know the factors that determine their release from foods, their extent of absorption, and their fate in the organism. Research on absorption, metabolism, and bioavailability of flavonoids will answer these questions. The subclass, flavonols, with quercetin as the major dietary flavonol, was the first to be studied, and information on other subclasses of flavonoids is emerging. Most flavonoids, except for the subclass of catechins, are present in plants bound to sugars as beta-glycosides. This structural feature determines whether the flavonoid can be absorbed from the small intestine or has to go to the colon before absorption can occur. Generally, but exceptions have been described, glucosides are the only glycosides that can be absorbed from the small intestine. Absorption from the small intestine is more efficient than from the colon and will lead to higher plasma values. After absorption from the small intestine, flavonoids are conjugated with glucuronic acid or sulfate or O-methylation may occur. The conjugation reactions, which occur in the small intestine upon absorption, are very efficient. As a result, no free flavonoid aglycones can be found in plasma or urine, except for catechins. Plasma concentrations due to a normal diet will be less than 1 microM. Flavonoids that cannot be absorbed from the small intestine, and absorbed flavonoids secreted with bile, will be degraded in the colon by microorganisms, which will break down the flavonoid ring structure. The resulting phenolic acids have partly been characterised. These phenolic acids can be absorbed and have been measured in plasma and urine. Future research will need to address tissue distribution, cellular uptake, and cellular metabolism.
Numerous numbers of biologically active agents have been identified for their diverse therapeutic functions. Detailed investigations of phytochemicals for antiviral activities have assumed greater importance in the last few decades. A wide variety of active phytochemicals, including the flavonoids, terpenoids, organosulfur compounds, limonoids, lignans, sulphides, polyphenolics, coumarins, saponins, chlorophyllins, furyl compounds, alkaloids, polyines, thiophenes, proteins and peptides have been found to have therapeutic applications against different genetically and functionally diverse viruses. The antiviral mechanism of these agents may be explained on basis of their antioxidant activities, scavenging capacities, inhibiting DNA, RNA synthesis, inhibition of the viral entry, or inhibiting the viral reproduction etc. Large number candidate substances such as phytochemicals and their synthetic derivatives have been identified by a combination of in vitro and in vivo studies in different biological assays. In this article we have made attempts to extensively review and provide comprehensive description of different phyto-antiviral agents. We have examined the recent developments in the field of plant derived antiviral agents. The major advances in the field of viral interactions in various biological assays have been summarized. In addition sources of origin, major viral studies mechanistic action and phase trials of various phytoantiviral agents have been included in the review.
To assess the possible effect of integrated traditional Chinese and Western medicine on severe acute respiratory syndromes.
The current available randomized controlled trials of integrated traditional Chinese and Western medicine on SARS were identified through systematically searching literature in any languages or any types of publications. Additional studies of gray literature were also collected. The quality of studies was evaluated by two investigators independently based largely on the quality criteria specified CONSORT. Statistical analysis of the results was performed using RevMan 4.2.0 software developed by the Cochrane Collaboration.
Six studies (n = 366) fulfilling the inclusion criteria were found, of which the quality of one study was graded as B, the remaining five were graded as C. Two studies were performed with meta-analysis, the other four studies existed some heterogeneity for which meta-analysis could not be performed, a significant effect on lung infiltrate absorption was found in the treatment groups of these two studies (RR 6.68, 95% CI (2.93, 15.24), P<0.01), there was no significant differences between the mortality (RR 0.86, 95% CI (0.22, 3.29), P = 0.82) and the average dosage of corticosteroid (WMD -39.65, 95% CI (-116.84, 37.54), P = 0.31). The other three studies also showed significant differences in infiltrate absorption, including national drug No. 2. 3. 4 in combination with Western medicine (RR 5.45, 95% CI (1.54, 19.26)), compound formulas NO. 1 combined with Western medicine (WMD 0.24, 95% CI (0.02, 0.46)), compound formulas combined with Western medicine (RR 8.06, 95% CI (0.40, 163.21)). Kangfeidian No.4 in combination with Western medicine had no significant effect on symptom improvement such as loss of dyspnea and cough (RR 1.50, 95%CI (0.41, 5.43)) and (RR 1.29, 95%CI (0.30, 5.43)).
Integrated traditional Chinese and Western medicines has some positive effects on lung infiltrate absorption in SARS patients, and is recommended as an adjunct treatment for SARS. However, its effect on SARS requires further careful study due to limited available randomized control trials.
Fourteen ORFs have been identified in the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) genome. ORF 3a of SARS-CoV codes for a recently identified transmembrane protein, but its function remains unknown. In this study we confirmed the 3a protein expression and investigated its localization at the surface of SARS-CoV-infected or 3a-cDNA-transfected cells. Our experiments showed that recombinant 3a protein can form a homotetramer complex through interprotein disulfide bridges in 3a-cDNA-transfected cells, providing a clue to ion channel function. The putative ion channel activity of this protein was assessed in 3a-complement RNA-injected Xenopus oocytes by two-electrode voltage clamp. The results suggest that 3a protein forms a potassium sensitive channel, which can be efficiently inhibited by barium. After FRhK-4 cells were transfected with an siRNA, which is known to suppress 3a expression, followed by infection with SARS-CoV, the released virus was significantly decreased, whereas the replication of the virus in the infected cells was not changed. Our observation suggests that SARS-CoV ORF 3a functions as an ion channel that may promote virus release. This finding will help to explain the highly pathogenic nature of SARS-CoV and to develop new strategies for treatment of SARS infection.
From the methanolic extract of Quercus ilex leaves a series of acylated flavonol glucosides (1-10) were identified, among them five new naturally occurring compounds. The constituents, which were all p-coumaroyl glucosides of kaempferol, were characterized either as pure compounds either as inseparable, complicated mixtures of cis and trans isomers. Their complete structure elucidation was done by 2D NMR (COSY, HSQC, HMBC, ROESY) and HPLC-DAD-MS analyses. 2D NMR spectral data allowed the discrimination between different isomers. Quantitative analysis of the methanolic extract of the plant revealed that it is a rich source of acylated flavonoid glucosides (1.22%). Under the experimental conditions chosen HPLC-DAD-MS analyses showed that cis isomers are less polar than trans isomers and their detailed identification, the first in the literature so far, could serve as a tool for the detailed characterization of analogous isomers by HPLC-DAD-MS in other complicated plant extracts.
1
R1 =A, R2=H, R3=H, R4=H
2
R1 =B, R2=H, R3=H, R4=H
3
R1 =A, R2=H, R3=H, R4=A
4
R1 =A, R2=H, R3=H, R4=B
5
R1 =B, R2=H, R3=H, R4=B
6
R1 =A, R2=C, R3=H, R4=A
7
R1 =A, R2=C, R3=H, R4=B
8
R1 =B, R2=C, R3=H, R4=B
9
R1 =A, R2=C, R3=C, R4=A
10
R1 =B, R2=C, R3=C, R4=B
The aim of this review, a summary of the putative biological actions of flavonoids, was to obtain a further understanding of the reported beneficial health effects of these substances. Flavonoids occur naturally in fruit, vegetables, and beverages such as tea and wine. Research in the field of flavonoids has increased since the discovery of the French paradox,ie, the low cardiovascular mortality rate observed in Mediterranean populations in association with red wine consumption and a high saturated fat intake. Several other potential beneficial properties of flavonoids have since been ascertained. We review the different groups of known flavonoids, the probable mechanisms by which they act, and the potential clinical applications of these fascinating natural substances.
Background:
Severe acute respiratory syndrome (SARS) is an acute respiratory disease caused by a novel coronavirus, which first appeared in Foshan City, China on 22 December 2002. Chinese herbs were used in its treatment.
Objectives:
To evaluate the possible effectiveness and safety of Chinese herbs combined with Western medicines versus Western medicines alone for SARS patients.
Search methods:
We searched CENTRAL 2012, Issue 3, MEDLINE (1966 to February Week 4, 2012), EMBASE (1990 to March 2012) and the Chinese Biomedical Literature (Issue 3, 2012).
Selection criteria:
Randomised controlled trials (RCTs) and quasi-RCTs of Chinese herbs combined with Western medicines versus Western medicines alone for patients diagnosed with SARS.
Data collection and analysis:
Two review authors (XL, MZ) independently extracted trial data. We extracted dichotomous and continuous data with 95% confidence intervals (CI). For dichotomous data, we used risk ratio (RR). For continuous data, we calculated mean differences (MD). We calculated overall results based on the random-effects model if heterogeneity existed between studies. If no heterogeneity was detected between the studies, we used the fixed-effect model. We used the Z score and the Chi(2) test with significance being set at P < 0.05 to test heterogeneity. No severe adverse events were reported.
Main results:
We included 12 RCTs and one quasi-RCT. A total of 640 SARS patients and 12 Chinese herbs were identified. We did not find Chinese herbs combined with Western medicines decreased mortality versus Western medicines alone. Two herbs may improve symptoms. Five herbs may improve lung infiltrate absorption. Four herbs may decrease the dosage of corticosteroids. Three herbs may improve the quality of life of SARS patients. One herb may shorten the length of hospital stay.
Authors' conclusions:
Chinese herbs combined with Western medicines made no difference in decreasing mortality versus Western medicines alone. It is possible that Chinese herbs combined with Western medicines may improve symptoms, quality of life and absorption of pulmonary infiltration, and decrease the corticosteroid dosage for SARS patients. The evidence is weak because of the poor quality of the included trials. Long-term follow-up of these included trials is needed.
The generation of computational models is an alternative route to obtain reliable structures for the oligomeric state of membrane proteins. A strategy has been developed to search the conformational space of all possible assemblies in a reasonable time, taking symmetry considerations into account. The methodology tested on M2 from influenza A, shows an excellent agreement with established structures. For Vpu from HIV-1 a series of conformational distinct structures are proposed. For the first time a structural model for a fully assembled transmembrane part of 3a from SARS-CoV is proposed.
The effect of several naturally occurring dietary flavonoids including quercetin, naringin, hesperetin, and catechin on the infectivity and replication of herpes simplex virus type 1 (HSV-I), polio-virus type 1, parainfluenza virus type 3 (Pf-3), and respiratory syncytial virus (RSV) was studied in vitro in cell culture monolayers employing the technique of viral plaque reduction. Quercetin caused a concentration-dependent reduction in the infectivity of each virus. In addition, it reduced intracellular replication of each virus when monolayers were infected and subsequently cultured in medium containing quercetin. Preincubation of tissue culture cell monolayers with quercetin did not affect the ability of the viruses to infect or replicate in the tissue culture monolayers. Hesperetin had no effect on infectivity but it reduced intracellular replication of each of the viruses. Catechin inhibited the infectivity but not the replication of RSV and HSV-1 and had negligible effects on the other viruses. Naringin had no effect on either the infectivity or the replication of any of the viruses studied. Thus, naturally occurring flavonoids possess a variable spectrum of antiviral activity against certain RNA (RSV, Pf-3, polio) and DNA (HSV-1) viruses acting to inhibit infectivity and/or replication.
The SARS coronavirus (CoV) positive-stranded RNA viral genome encodes 14 open reading frames (ORFs), eight of which encode
proteins termed as “accessory proteins.” These proteins help the virus infect the host and promote virulence. In this chapter
we describe some of our latest investigations into the structure and function of two such accessory proteins: ORF3a and 9b.
The ORF3a accessory protein is the largest accessory protein in SARS-CoV and is a unique membrane protein consisting of three
transmembrane domains. It colocalizes on the cell membrane and host Golgi networks and may be involved in ion channel formation
during infection. Similarly the ORF9b accessory protein is 98 amino acids, associates with the spike and nucleocapsid proteins
and has unusual membrane binding properties. In this chapter we have suggested possible new roles for these two accessory
proteins which may in the long run contain answers to many unanswered questions and also give us new ideas for drugs and vaccine
design.
From the methanolic extract of Quercus ilex leaves a series of acylated flavonol glucosides were identified, among them five new naturally occurring compounds. The constituents, which were all p-coumaroyl glucosides of kaempferol, were characterised either as pure compounds or as inseparable, complicated mixtures of cis and trans isomers. Their complete structure elucidation was done by 2D NMR (COSY, HSQC, HMBC, ROESY) and HPLC-DAD-MS analyses. 2D NMR spectral data allowed the discrimination between different isomers. Quantitative analysis of the methanolic extract of the plant revealed that it is a rich source of acylated flavonoid glucosides (1.22%). Under the experimental conditions chosen HPLC-DAD-MS analyses showed that cis isomers are less polar than trans isomers and their detailed identification, the first in the literature so far, could serve as a tool for the detailed characterisation of analogous isomers by HPLC-DAD-MS in other complicated plant extracts.
The novel small molecule, BIT225 (N-[5-(1-methyl-1H-pyrazol-4-yl)-napthalene-2-carbonyl]-guanidine: CAS No. 917909-71-8), was initially identified using a screening strategy designed to detect inhibitors of Hepatitis C virus (HCV) p7 ion channel activity. Here we report that BIT225 has potent stand-alone antiviral activity against the HCV model pestivirus bovine viral diarrhea virus (BVDV) with an IC50 of 314 nM. Combinations of BIT225 with recombinant interferon alpha-2b (rIFNα-2b) show synergistic antiviral action against BVDV and the synergy is further enhanced by addition of ribavirin. Synergy was also observed between BIT225 and two nucleoside analogues known to inhibit the HCV RNA-dependent RNA polymerase.BIT225 has successfully completed a phase Ia dose escalating, single dose safety trial in healthy volunteers and a phase Ib/IIa trial to evaluate the safety and pharmacokinetics of repeated dosing for selected doses of BIT225 in HCV-infected persons. A modest, but statistically significant drop in patient viral load was detected over the 7 days of dosing (ref. www.biotron.com.au). Given the critical role of the p7 protein in the HCV life cycle and pathogenicity, our data indicate that molecules like BIT225, representing a new class of antiviral compounds, may be developable for therapeutic use against HCV infection, either as monotherapy, or in combination with other HCV drugs.
Viral channel-forming proteins comprise a class of viral proteins which, similar to their host companions, are made to alter electrochemical or substrate gradients across lipid membranes. These proteins are active during all stages of the cellular life cycle of viruses. An increasing number of proteins are identified as channel proteins, but the precise role in the viral life cycle is yet unknown for the majority of them. This review presents an overview about these proteins with an emphasis on those with available structural information. A concept is introduced which aligns the transmembrane domains of viral channel proteins with those of host channels and toxins to give insights into the mechanism of function of the viral proteins from potential sequence identities. A summary of to date investigations on drugs targeting these proteins is given and discussed in respect of their mode of action in vivo.
Flavonoids are polyphenolic compounds that widely exist in plant kingdom, and the structure-activity relationship (SAR) of 25 flavonoids was studied on neuraminidase (NA) activity of influenza virus. Three typical influenza virus strains A/PR/8/34 (H1N1), A/Jinan/15/90 (H3N2), and B/Jiangshu/10/2003 were used as the source of NAs, the average of IC(50)s of these compounds on these NAs was used in the SAR analysis. The order of potency for NA inhibition was as follows: aurones>flavon(ol)es>isoflavones>flavanon(ol)es and flavan(ol)es. The SAR analysis of flavonoids on influenza virus NAs revealed that for good inhibitory effect, the 4'-OH, 7-OH, C4O, and C2C3 functionalities were essential, and the presence of a glycosylation group greatly reduced NA inhibition. The in vitro anti-viral activities of eight flavonoids were evaluated using a cytopathic effect (CPE) reduction method, the assay results confirmed the SAR as influenza virus neuraminidase inhibitors. The findings of this study provide important information for the exploitation and utilization of flavonoids as NA inhibitors for influenza treatment.
Oogenesis in the anuran Xenopus laevis can be divided into six stages based on the anatomy of the developing oocyte. Stage I consists of small (50 to 100 μ) colorless oocytes whose cytoplasm is transparent. Their large nuclei and mitochondrial masses are clearly visible in the intact oocyte. Stage II oocytes range up to 450 μ in diameter, and appear white and opaque. Stage I and II are both previtellogenic. Pigment synthesis and yolk accumulation (vitellogenesis) begins during Stage III. Vitellogenesis continues through Stage IV (600 to 1000 μ), the oocytes grow rapidly, and the animal and vegetal hemispheres become differentiated. By Stage V (1000 to 1200 μ) the oocytes have nearly reached their maximum size and yolk accumulation gradually ceases. Stage VI oocytes are characterized by the appearance of an essentially unpigmented equatorial band. They range in size from 1200 to 1300 μ, are postivtellogenic and ready for ovulation. These stages of oocyte development have been correlated with physiological and biochemical data related to oogenesis in Xenopus.
In the present study, a method based on liquid chromatography with diode array detection (HPLC-DAD) coupled to an electrospray ionisation (ESI) interface was developed for the determination of the constituents in the aqueous preparations of Viola odorata L. flowering tops. The developed assay was fast, simple and effective and permitted the quality control of the preparations. The aim of this work was to assess the qualitative and quantitative profile of the investigated preparations, which find until today wide applications in food and cosmetic industry, and to propose a validated method for their quality control. Characteristic constituents of V. odorata flowers are considered to be the anthocyanins; however, a detailed literature research showed that data concerning their chemical content are scarce. HPLC-DAD-ESI-MS analyses supported by extensive preparative chromatographic investigations and 2D NMR analyses revealed the predominance of complex flavonol glycosides and permitted the complete characterisation of the content of V. odorata preparations. This is the first report of detailed analysis of the chemical composition of V. odorata flowers.
Viral ion channels are short membrane proteins with 50-120 amino acids and play an important role either in regulating virus replication, such as virus entry, assembly and release or modulating the electrochemical balance in the subcellular compartments of host cells. This review summarizes the recent advances in viral encoded ion channel proteins (or viroporins), including PBCV-1 KcV, influenza M2, HIV-1 Vpu, HCV p7, picornavirus 2B, and coronavirus E and 3a. We focus on their function and mechanisms, and also discuss viral ion channel protein serving as a potential drug target.
Ca(2+) is one of the most universal and versatile signaling molecules and is involved in almost every aspect of cellular processes. Viruses are adept at utilizing the universal Ca(2+) signal to create a tailored cellular environment that meets their own demands. This review summarizes most of the known mechanisms by which viruses perturb Ca(2+) homeostasis and utilize Ca(2+) and cellular Ca(2+)-binding proteins to their benefit in their replication cycles. Ca(2+) plays important roles in virion structure formation, virus entry, viral gene expression, posttranslational processing of viral proteins and virion maturation and release. As part of the review, we introduce an algorithm to identify linear "EF-hand" Ca(2+)-binding motifs which resulted in the prediction of a total of 93 previously unrecognized Ca(2+)-binding motifs in virus proteins. Many of these proteins are nonstructural proteins, a class of proteins among which Ca(2+) interactions had not been formerly appreciated. The presence of linear Ca(2+)-binding motifs in viral proteins enlarges the spectrum of Ca(2+)-virus interplay and expands the total scenario of viral calciomics.
The clinical treatment of neoplastic diseases relies on the complementary procedures of surgery, radiation treatment, immunotherapy and chemotherapy. The latter technique has matured from its earliest applications of mustard alkylating agents in the 1940s to an increasingly rationally based discipline, which is contributing significantly to the management of human malignancies. As the field of chemotherapy matured, several promising natural anticancer agents were identified. However, a more urgent need soon arose from the common experience of clinically limiting toxicities of most anticancer drugs, i.e. the necessity to develop less toxic clinical drug candidates. Thus, the medicinal chemist turned towards analog development involving certain anthraquinones. Hand-in-hand with this considerable synthetic effort, which uncovered several promising clinical leads, biochemical pharmacology, or study of the mechanisms of action of clinical anticancer agents, afforded deeper insight into drug metabolism and mode of action. More recently, therefore, the field of synthetic organic chemistry, which has been complemented by the methods of microbial chemistry, has been faced with new synthetic challenges, occasioned by the identification of hitherto unrecognized cellular targets for anticancer drugs, such as topoisomerases and helicases. The armementarium of the oncologist currently includes about 40-50 clinically useful chemical agents. The paradigm of cytotoxic anticancer agents is doxorubicin, an anthracycline, which is still amongst the most widely prescribed and effective of anticancer agents. The review attempts to summarize the discovery of anthracyclines and the elucidation of their several mechanisms of action and efforts towards improvement of their therapeutic efficacy.
The antiviral activity of seven flavonoids, belonging to the kaempferol series, was evaluated against human cytomegalovirus (HCMV) by a rapid method of detection of the immediate-early (IE) antigen, induced by the virus in infected cells. Flavonoids bearing acyl substituents were found to be the most active compounds.
This review summarizes the types of evidence that can be invoked in order to demonstrate that a virally encoded protein possesses ion channel activity that is intrinsic to the life cycle of the virus. Ion channel activity has been proposed to be a key step in the life cycle of influenza virus, and the protein responsible for this activity has been proposed to be the M2 protein encoded by the virus. This review contrasts the evidence supporting the conclusion that the A/M2 protein of influenza A virus has intrinsic ion channel activity with the evidence that the 3AB protein encoded by the human rhinovirus possesses intrinsic ion channel activity.
Vpu, a membrane protein from human immunodeficiency virus-1, folds into two distinct structural domains with different biological activities: a transmembrane (TM) helical domain involved in the budding of new virions from infected cells, and a cytoplasmic domain encompassing two amphipathic helices, which is implicated in CD4 degradation. The molecular mechanism by which Vpu facilitates virion budding is not clear. This activity of Vpu requires an intact TM helical domain. And it is known that oligomerization of the VPU TM domain results in the formation of sequence-specific, cation-selective channels. It has been shown that the channel activity of Vpu is confined to the TM domain, and that the cytoplasmic helices regulate the lifetime of the Vpu channel in the conductive state. Structure-function correlates based on the convergence of information about the channel activity of Vpu reconstituted in lipid bilayers and on its 3-D structure in membranes by a combination of solution and solid-state nuclear magnetic resonance spectroscopy may provide valuable insights to understand the role of Vpu in the pathogenesis of AIDS and for drug design aimed to block channel activity.
We report antiviral activity against human cytomegalovirus for certain dietary flavonoids and their likely biochemical mechanisms of action. Nine out of ten evaluated flavonoids blocked HCMV replication at concentrations that were significantly lower than those producing cytotoxicity against growing or stationary phase host cells. Baicalein was the most potent inhibitor in this series (IC(50)=0.4-1.2 microM), including positive control ganciclovir. Baicalein and genistein were chosen as model compounds to study the antiviral mechanism(s) of action for this series. Both flavonoids significantly reduced the levels of HCMV early and late proteins, as well as viral DNA synthesis. Baicalein reduced the levels of HCMV immediate-early proteins to nearly background levels while genistein did not. The antiviral effects of genistein, but not baicalein, were fully reversible in cell culture. Pre-incubation of concentrated virus stocks with either flavonoid did not inhibit HCMV replication, suggesting that baicalein did not directly inactivate virus particles. Baicalein functionally blocked epidermal growth factor receptor tyrosine kinase activity and HCMV nuclear translocation, while genistein did not. At 24h post infection HCMV-infected cells treated with genistein continued to express immediate-early proteins and efficiently phosphorylate IE1-72. However, HCMV induction of NF-kappaB and increases in the levels of cell cycle regulatory proteins--events that are associated with immediate-early protein functioning--were absent. The data suggested that the primary mechanism of action for baicalein may be to block HCMV infection at entry while the primary mechanism of action for genistein may be to block HCMV immediate-early protein functioning.
Flavonoids, a group of low molecular weight phenylbenzopyrones, have various pharmacological properties including antioxidant, anticancer, bactericidal, and anti-inflammatory. We carried out anti-herpetic assays on 18 flavonoids in five classes and a virus-induced cytopathic effect (CPE) inhibitory assay, plaque reduction assay, and yield reduction assay were performed. When flavonoids were applied at various concentrations to Vero cells infected by HSV-1 and 2, most of the flavonoids showed inhibitory effects on virus-induced CPE. Among the flavonoids, EC, ECG (flavanols), genistein (isoflavone), naringenin (flavanone), and quercetin (flavonol) showed a high level of CPE inhibitory activity. The antiviral activity of flavonoids were also examined by a plaque reduction assay. EC, ECG, galangin, and kaempferol showed a strong antiviral activity, and catechin, EGC, EGCG, naringenin, chrysin, baicalin, fisetin, myricetin, quercetin, and genistein showed moderate inhibitory effects against HSV-1. In these experiments, flavanols and flavonols appeared to be more active than flavones. Furthermore, treatment of Vero cells with ECG and galangin (which previously showed strong antiviral activities) before virus adsorption led to a slight enhancement of inhibition as determined by a yield reduction assay, indicating that an intracellular effect may also be involved.
Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel coronavirus (SARS-CoV). SARS-CoV spike (S) protein, a type I membrane-bound protein, is essential for the viral attachment to the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening 312 controlled Chinese medicinal herbs supervised by Committee on Chinese Medicine and Pharmacy at Taiwan, we identified that three widely used Chinese medicinal herbs of the family Polygonaceae inhibited the interaction of SARS-CoV S protein and ACE2. The IC(50) values for Radix et Rhizoma Rhei (the root tubers of Rheum officinale Baill.), Radix Polygoni multiflori (the root tubers of Polygonum multiflorum Thunb.), and Caulis Polygoni multiflori (the vines of P. multiflorum Thunb.) ranged from 1 to 10 microg/ml. Emodin, an anthraquinone compound derived from genus Rheum and Polygonum, significantly blocked the S protein and ACE2 interaction in a dose-dependent manner. It also inhibited the infectivity of S protein-pseudotyped retrovirus to Vero E6 cells. These findings suggested that emodin may be considered as a potential lead therapeutic agent in the treatment of SARS.
All coronaviruses encode a small hydrophobic envelope (E) protein, which mediates viral assembly and morphogenesis by an unknown mechanism. We have previously shown that the E protein from Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) forms cation-selective ion channels in planar lipid bilayers (Wilson, L., McKinlay, C., Gage, P., Ewart, G., 2004. SARS coronavirus E protein forms cation-selective ion channels. Virology 330(1), 322-331). We now report that three other E proteins also form cation-selective ion channels. These E proteins were from coronaviruses representative of taxonomic groups 1-3: human coronavirus 229E (HCoV-229E), mouse hepatitis virus (MHV), and infectious bronchitis virus (IBV), respectively. It appears, therefore, that coronavirus E proteins in general, belong to the virus ion channels family. Hexamethylene amiloride (HMA)--an inhibitor of the HIV-1 Vpu virus ion channel--inhibited the HCoV-229E and MHV E protein ion channel conductance in bilayers and also inhibited replication of the parent coronaviruses in cultured cells, as determined by plaque assay. Conversely, HMA had no antiviral effect on a recombinant MHV with the entire coding region of E protein deleted (MHVDeltaE). Taken together, the data provide evidence of a link between inhibition of E protein ion channel activity and the antiviral activity of HMA.
The 3C-like protease (3CL(pro)) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for discovery of drugs against SARS, because of its critical role in the viral life cycle. In this study, a natural compound called quercetin-3-beta-galactoside was identified as an inhibitor of the protease by molecular docking, SPR/FRET-based bioassays, and mutagenesis studies. Both molecular modeling and Q189A mutation revealed that Gln189 plays a key role in the binding. Furthermore, experimental evidence showed that the secondary structure and enzymatic activity of SARS-CoV 3CL(pro) were not affected by the Q189A mutation. With the help of molecular modeling, eight new derivatives of the natural product were designed and synthesized. Bioassay results reveal salient features of the structure-activity relationship of the new compounds: (1) removal of the 7-hydroxy group of the quercetin moiety decreases the bioactivity of the derivatives; (2) acetoxylation of the sugar moiety abolishes inhibitor action; (3) introduction of a large sugar substituent on 7-hydroxy of quercetin can be tolerated; (4) replacement of the galactose moiety with other sugars does not affect inhibitor potency. This study not only reveals a new class of compounds as potential drug leads against the SARS virus, but also provides a solid understanding of the mechanism of inhibition against the target enzyme.
The benefits of flavonoids as chemopreventive dietary or dietary supplemental agents are still only "potential." Much has been learned about possible mechanisms of action of these agents, but whether they can reach their multiple intended sites of action, particularly in humans, is largely unknown. The biological fate of the flavonoids, including their dietary glycoside forms, is highly complex, dependent on a large number of processes. This review is intended to bring some order into this complex area and deals with the fate of the naturally occurring glycosides, their enzymatic hydrolysis, as well as the resulting aglycones. The impact of membrane transporters as well as metabolic enzymes on the cellular availability of these phytochemicals is examined. A reevaluation of the concept of oral bioavailability applied to the dietary flavonoids is presented.
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