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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
... 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.
... Activity of plant phenolics against ORF3a has been reported in the literature: kaempferol and its glycosylated derivative juglanin inhibit ORF3a activity of SARS-CoV expressed in Xenopus oocytes, while naringenin and genistein do not 36 . The same study reported very little inhibition of ORF3a by quercetin 36 , as also observed here. ...
... Activity of plant phenolics against ORF3a has been reported in the literature: kaempferol and its glycosylated derivative juglanin inhibit ORF3a activity of SARS-CoV expressed in Xenopus oocytes, while naringenin and genistein do not 36 . The same study reported very little inhibition of ORF3a by quercetin 36 , as also observed here. Antiviral activity of phenolics has been reported. ...
SARS-CoV-2 has been responsible for the major worldwide pandemic of COVID-19. Despite the enormous success of vaccination campaigns, virus infections are still prevalent and effective antiviral therapies are urgently needed. Viroporins are essential for virus replication and release, and are thus promising therapeutic targets. Here, we studied the expression and function of recombinant ORF3a viroporin of SARS-CoV-2 using a combination of cell viability assays and patch-clamp electrophysiology. ORF3a was expressed in HEK293 cells and transport to the plasma membrane verified by a dot blot assay. Incorporation of a membrane-directing signal peptide increased plasma membrane expression. Cell viability tests were carried out to measure cell damage associated with ORF3a activity, and voltage-clamp recordings verified its channel activity. The classical viroporin inhibitors amantadine and rimantadine inhibited ORF3a channels. A series of ten flavonoids and polyphenolics were studied. Kaempferol, quercetin, epigallocatechin gallate, nobiletin, resveratrol and curcumin were ORF3a inhibitors, with IC50 values ranging between 1 and 6 µM, while 6-gingerol, apigenin, naringenin and genistein were inactive. For flavonoids, inhibitory activity could be related to the pattern of OH groups on the chromone ring system. Thus, the ORF3a viroporin of SARS-CoV-2 may indeed be a promising target for antiviral drugs.
... 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.
... Most in vitro and in vivo studies are in progress for screening the effectiveness of phytochemicals against coronaviruses (especially SARS-CoV-2), computer docking models studies on predicting the anti-CoVs effects of these compounds against the coronavirus family members such as SARS-CoV, MERS-CoV, and SARS-CoV-2. Research showed that natural polyphenol compounds like quercetin (Chiow et al., 2016), kaempferol (Schwarz et al., 2014), myricetin (Yu et al., 2012), apigenin (Ryu et al., 2010a), and resveratrol (Wahedi et al., 2020) hold prominent activities against coronaviruses. Lung injury is the main COVID-19 complication that happens with inflammatory cascades by SARS-CoV-2 (Fakhri et al., 2020). ...
... The results reported by Peng et al. [41] showed that myricetin exhibits antiviral activity against avian infectious bronchitis virus by inhibiting the deubiquitinating activity of papain-like protease. Kaempferol glycosides can block the 3a channel of coronaviruses, preventing the production of the virus [42]. Emodin exhibits antiviral activity against coronavirus by disrupting S-protein interaction with the angiotensin-converting enzyme 2 receptor (ACE2) [43]. ...
This paper discusses the possibility of using plant polyphenols as viral fusion inhibitors with a lipid-mediated mechanism of action. The studied agents are promising candidates for the role of antiviral compounds due to their high lipophilicity, low toxicity, bioavailability, and relative cheapness. Fluorimetry of calcein release at the calcium-mediated fusion of liposomes, composed of a ternary mixture of dioleoyl phosphatidylcholine, dioleoyl phosphatidylglycerol, and cholesterol, in the presence of 4′-hydroxychalcone, cardamonin, isoliquiritigenin, phloretin, resveratrol, piceatannol, daidzein, biochanin A, genistein, genistin, liquiritigenin, naringenin, catechin, taxifolin, and honokiol, was performed. It was found that piceatannol significantly inhibited the calcium-induced fusion of negatively charged vesicles, while taxifolin and catechin showed medium and low antifusogenic activity, respectively. As a rule, polyphenols containing at least two OH-groups in both phenolic rings were able to inhibit the calcium-mediated fusion of liposomes. In addition, there was a correlation between the ability of the tested compounds to inhibit vesicle fusions and to perturb lipid packing. We suggest that the antifusogenic action of polyphenols was determined by the depth of immersion and the orientation of the molecules in the membrane.
... Fruits, vegetables, whole grains, legumes, nuts, seeds, spices, and teas are rich in the flavonoid class of polyphenols (examples in Figure 1A), which may contribute to positive outcomes after SARS-CoV-2 infection through direct and indirect mechanisms. Parent polyphenols (PPs) and their microbial metabolites (MMs) have antiviral, antibacterial, anti-inflammatory, and antioxidant properties (Kaihatsu et al., 2018;Kuhn et al., 2018;Lee et al., 2012;Schwarz et al., 2014;Wu et al., 2015;Xu et al., 2017;Yahfoufi et al., 2018;Zhou et al., 2015). Consumption of plant foods rich in polyphenols is correlated with lower risk of comorbidities that worsen COVID-19 symptoms such as obesity, diabetes, hypertension, and cardiovascular disease (Del Bo' et al., 2019). ...
The outcome of SARS-CoV-2 infection ranges from asymptomatic to severe COVID-19 and death resulting from an exaggerated immune response termed cytokine storm. Epidemiological data have associated consumption of a high-quality plant-based diet with decreased incidence and severity of COVID-19. Dietary polyphenols and their microbial metabolites (MMs) have anti-viral and anti-inflammatory activities. Autodock Vina and Yasara were used in molecular docking and dynamics studies to investigate potential interactions of 7 parent polyphenols (PPs) and 11 MMs with the α- and Omicron variants of the SARS-CoV-2 spike glycoprotein (SGP), papain-like pro-tease (PLpro) and 3 chymotrypsin-like protease (3CLpro), as well as host inflammatory mediators including complement component 5a (C5a), C5a receptor (C5aR), and C-C chemokine receptor type 5 (CCR5). PPs and MMs interacted to varying degrees with residues on target viral and host inflammatory proteins showing potential as competitive inhibitors. Based on these in silico findings, PPs and MMs may inhibit SARS-CoV-2 infection, replication, and/or modulate host immunity in the gut or periphery. Such inhibition may explain why people that consume a high-quality plant-based diet have less incidence and severity of COVID-19.
Communicated by Ramaswamy H. Sarma
... Finally, Schwarz et al. [69] based their research on the fact that the protein coded by the open-reading-frame 3a of SARS coronavirus forms a cation-selective channel that may become expressed in the infected cell, and the activity of the channel is involved in the mechanism of virus release. In this way, the authors tested the flavonols kaempferol, kaempferol glycosides and acylated kaempferol glucoside derivatives from the leaves of the plant Quercus ilex L. and kaempferol triglycoside from Viola odorata L. for their capacity to block the 3a channel and, therefore, inhibit virus release. ...
The recent pandemic of COVID-19 caused by the SARS-CoV-2 virus has brought upon the world an unprecedented challenge. During its acute dissemination, a rush for vaccines started, making the scientific community come together and contribute to the development of efficient therapeutic agents and vaccines. Natural products have been used as sources of individual molecules and extracts capable of inhibiting/neutralizing several microorganisms, including viruses. Natural extracts have shown effective results against the coronavirus family, when first tested in the outbreak of SARS-CoV-1, back in 2002. In this review, the relationship between natural extracts and SARS-CoV is discussed, while also providing insight into misinformation regarding the use of plants as possible therapeutic agents. Studies with plant extracts on coronaviruses are presented, as well as the main inhibition assays and trends for the future regarding the yet unknown long-lasting effects post-infection with SARS-CoV-2.
... The method useful in the early stage of the infection was used as coadjuvant therapy for SARS-CoV infection (Rosa and Santos, 2020). According to the previous research, it has been reported that baicalin derived from Scutellaria baicalensis is known to have anti-SARS activity (Chen and Nakamura, 2004;Deng et al., 2012), glycyrrhizin a major active constituent of Liquorice root and tetra-o-galloylβ-D-glucose and luteolin obtained from Galla chinensis and Veronicalina riifolia respectively (Yi et al., 2004), as well as Kaempferol derivatives (Schwarz et al., 2014) is the most frequently used Chinese herb and effectively inhibit the replication of SARS virus. Various other herbal compounds such as sinigrin, indigo, aloe-emodin (derived from genus Rheum and Polygonum) (Schwarz et al., 2011), hesperetin, herbacetin, quercetin, rhoifolin, andpectolinarin (Nguyen et al., 2012) are also known to have potential anti-SARS CoV activity (Fig. 2). ...
... Yosri et al. [33], observed that such anti-viral effects are also exhibited by broussoflavonol F, chrysin, glyasperin A, kaempferol, sulabiroins A, caffeic acid, 3-phenyllactic acid, lumichrome. Moreover, various secondary metabolites exhibit antiviral action; specifically, phenolic compounds (inhibit the activity of SARS-3CLpro enzyme), quercetin (inhibits the cellular entry of SARS-CoV and the activity of SARS-CoV 3CLpro), kaempferol (inhibits the 3a ion channel of coronavirus), luteolin (binds the surface spike protein of SARS-CoV), apigenin and luteolin (inhibit the activity of SARS-CoV 3CLpro), [13,[43][44][45]. Additionally, chrysin exhibited antiviral activity (via the inhibition of viral capsid protein production and the RNA replication of enterovirus 71) [46]. ...
Propolis remains an interesting source of natural chemical compounds that show, among others, antibacterial, antifungal, antiviral, antioxidative and anti-inflammatory activities. Due to the growing incidence of respiratory tract infections caused by various pathogenic viruses, complementary methods of prevention and therapy supporting pharmacotherapy are constantly being sought out. The properties of propolis may be important in the prevention and treatment of respiratory tract diseases caused by viruses such as severe acute respiratory syndrome coronavirus 2, influenza viruses, the parainfluenza virus and rhinoviruses. One of the main challenges in recent years has been severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing COVID-19. Recently, an increasing number of studies are focusing on the activity of various propolis preparations against SARS-CoV-2 as an adjuvant treatment for this infection. Propolis has shown a few key mechanisms of anti-SARS-CoV-2 action such as: the inhibition of the interaction of the S1 spike protein and ACE-2 protein; decreasing the replication of viruses by diminishing the synthesis of RNA transcripts in cells; decreasing the particles of coronaviruses. The anti-viral effect is observed not only with extracts but also with the single biologically active compounds found in propolis (e.g., apigenin, caffeic acid, chrysin, kaempferol, quercetin). Moreover, propolis is effective in the treatment of hyperglycemia, which increases the risk of SARS-CoV-2 infections. The aim of the literature review was to summarize recent studies from the PubMed database evaluating the antiviral activity of propolis extracts in terms of prevention and the therapy of respiratory tract diseases (in vitro, in vivo, clinical trials). Based upon this review, it was found that in recent years studies have focused mainly on the assessment of the effectiveness of propolis and its chemical components against COVID-19. Propolis exerts wide-spectrum antimicrobial activities; thus, propolis extracts can be an effective option in the prevention and treatment of co-infections associated with diseases of the respiratory tract.
... Among these components, Quercetin, Wogonin, and Emodin were able to interfere with various stages of the coronavirus entry and replication cycle (59,81,82). Kaempferol could be used as an antiviral drug against the 3a Channel Protein of Coronavirus (55). Baicalein had a high affinity for SARS-CoV-2 3CLpro (83). ...
Introduction
Coronavirus Disease-2019 (COVID-19) is an infectious disease caused by SARS-CoV-2. Severe cases of COVID-19 are characterized by an intense inflammatory process that may ultimately lead to organ failure and patient death. Qingfei Paidu Decoction (QFPD), a traditional Chines e medicine (TCM) formula, is widely used in China as anti-SARS-CoV-2 and anti-inflammatory. However, the potential targets and mechanisms for QFPD to exert anti-SARS-CoV-2 or anti-inflammatory effects remain unclear.
Methods
In this study, Computer-Aided Drug Design was performed to identify the antiviral or anti-inflammatory components in QFPD and their targets using Discovery Studio 2020 software. We then investigated the mechanisms associated with QFPD for treating COVID-19 with the help of multiple network pharmacology approaches.
Results and discussion
By overlapping the targets of QFPD and COVID-19, we discovered 8 common targets (RBP4, IL1RN, TTR, FYN, SFTPD, TP53, SRPK1, and AKT1) of 62 active components in QFPD. These may represent potential targets for QFPD to exert anti-SARS-CoV-2 or anti-inflammatory effects. The result showed that QFPD might have therapeutic effects on COVID-19 by regulating viral infection, immune and inflammation-related pathways. Our work will promote the development of new drugs for COVID-19.
... Drugs that block the viral coded channels prevent the virus from being released from infected cells, which prevents the virus from spreading to other host cells. [68]. ...
Flavonoids, a naturally occurring substance that is extensively spread across the plant kingdom, are what give plants their diverse hues in the form of leaves, flowers, fruits, and seeds. These have strong antioxidant effects and are secondary metabolites of plants. Sedative, antioxidant, anticonvulsant, antidepressant, anti-inflammatory, anti-cancer, anti-microbial, antihypertensive, Vasorelaxant, cardiac protective, antidiuretic, antiulcerogenic, anti-fungal, antiviral, Antineoplastic, Neuroprotective, and Hepatoprotective properties are all possessed by flavonoids. Numerous studies have shown that its antioxidant property is primarily responsible for the pharmacological effects indicated above. As a result of their influence on mammalian enzymes such protein kinases, aldose reductase, and alpha-glucosidase flavonoids regulate a number of cellular signaling pathways that get disrupted under pathological situations. Due to their many health benefits, flavonoids are the subject of numerous ongoing studies. A variety of flavonoids are sold as pharmaceutical goods on the market due to their advantages in terms of cost-effective mass manufacture and health advantages. The classification, metabolic, pharmacological, and biological effects of flavonoid supplements sold on the market are the main topics of the current review.
... Based on previous findings, genistin, kaempferol, mellein, rhoifolin and scutellarein have shown antiviral properties at a clinical scale on various viral pathogens. Genistin has been proven to exhibit antiviral activity against Herpes B Virus (LeCher et al., 2019) while kaempferol showed antiviral druggability against the 3a channel protein of coronavirus (Schwarz et al., 2014). On the other hand, mellein has shown antiviral activity against influenza and Herpes simplex viruses (Zgórniak-Nowosielska et al., 1991) and rhoifolin inhibit the SARS-CoV 3CL protease (Russo et al., 2020). ...
Background
Pea eggplant ( Solanum torvum Swartz) commonly known as turkey berry or ‘ terung pipit’ in Malay is a vegetable plant widely consumed by the local community in Malaysia. The shrub bears pea-like turkey berry fruits (TBFs), rich in phytochemicals of medicinal interest. The TBF phytochemicals hold a wide spectrum of pharmacological properties. In this study, the TBF phytochemicals’ potential inhibitory properties were evaluated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) of the Coronavirus disease 2019 (COVID-19). The TBF polyphenols were screened against SARS-CoV receptors via molecular docking and the best receptor-ligand complex was validated further by molecular dynamics (MD) simulation.
Method
The SARS-CoV receptor structure files (viral structural components) were retrieved from the Protein Data Bank (PDB) database: membrane protein (PDB ID: 3I6G), main protease (PDB ID: 5RE4), and spike glycoproteins (PDB ID: 6VXX and 6VYB). The receptor binding pocket regions were identified by Discovery Studio (BIOVIA) for targeted docking with TBF polyphenols (genistin, kaempferol, mellein, rhoifolin and scutellarein). The ligand and SARS-CoV family receptor structure files were pre-processed using the AutoDock tools. Molecular docking was performed with the Lamarckian genetic algorithm using AutoDock Vina 4.2 software. The best pose (ligand-receptor complex) from the molecular docking analysis was selected based on the minimum binding energy (MBE) and extent of structural interactions, as indicated by BIOVIA visualization tool. The selected complex was validated by a 100 ns MD simulation run using the GROMACS software. The dynamic behaviour and stability of the receptor-ligand complex were evaluated by the root mean square displacement (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), solvent accessible surface volume (SASV) and number of hydrogen bonds.
Results
At RMSD = 0, the TBF polyphenols showed fairly strong physical interactions with SARS-CoV receptors under all possible combinations. The MBE of TBF polyphenol-bound SARS CoV complexes ranged from −4.6 to −8.3 kcal/mol. Analysis of the structural interactions showed the presence of hydrogen bonds, electrostatic and hydrophobic interactions between the receptor residues (RR) and ligands atoms. Based on the MBE values, the 3I6G-rhoifolin (MBE = −8.3 kcal/mol) and 5RE4-genistin (MBE = −7.6 kcal/mol) complexes were ranked with the least value. However, the latter showed a greater extent of interactions between the RRs and the ligand atoms and thus was further validated by MD simulation. The MD simulation parameters of the 5RE4-genistin complex over a 100 ns run indicated good structural stability with minimal flexibility within genistin binding pocket region. The findings suggest that S. torvum polyphenols hold good therapeutics potential in COVID-19 management.
... Anti-HIV drugs such as zidovudine (AZT) are also potent inhibitors of EBV replication [42] which are phosphorylated by EBV thymidine kinase [43]. Moreover, the benzimidazole derivative maribavir possesses dual anti-EBV functions: termination of viral replication and inhibition of viral kinase activity [44]. The second category includes anti-reactivation agents. ...
Kaempferol (KP, 3,4′,5,7-tetrahydroxyflavone), a dietary flavonol, has anti-cancer, antioxidant, anti-inflammatory, antimicrobial, and antimutagenic functions. However, it is unknown whether kaempferol possesses anti-Epstein–Barr virus (EBV) activity. Previously, we demonstrated that inhibition of EBV reactivation represses nasopharyngeal carcinoma (NPC) tumourigenesis, suggesting the importance of identifying EBV inhibitors. In this study, Western blotting, immunofluorescence staining, and virion detection showed that kaempferol repressed EBV lytic gene protein expression and subsequent virion production. Specifically, kaempferol was found to inhibit the promoter activities of Zta and Rta (Zp and Rp) under various conditions. A survey of the mutated Zp constructs revealed that Sp1 binding regions are critical for kaempferol inhibition. Kaempferol treatment repressed Sp1 expression and decreased the activity of the Sp1 promoter, suggesting that Sp1 expression was inhibited. In conclusion, kaempferol efficiently inhibits EBV reactivation and provides a novel choice for anti-EBV therapy and cancer prevention.
... Kaempferol possesses a chemical structure similar to that of quercetin. Other studies showed that quercetin and kaempferol had antiviral activities against SARS-CoV-2 which were mediated through inhibiting protein kinase B, phosphorylating of protein kinase, and blocking of the 3a channel [50][51][52]. The two compounds also regulated immune responses by reducing pro-inflammatory cytokines and enhancing anti-inflammatory cytokines, which have been proved to have a positive effect on COVID-19 treatment [53][54][55][56]. ...
Background:
A new viral outbreak caused by monkeypox has appeared after COVID-19. As of yet, no specific drug has been found for its treatment. Shengma-Gegen decoction (SMGGD), a pathogen-eliminating and detoxifying agent composed of four kinds of Chinese herbs, has been demonstrated to be effective against several viruses in China, suggesting that it may be effective in treating monkeypox, however, the precise role and mechanisms are still unknown.
Methods:
Network pharmacology was used to investigate the monkeypox-specific SMGGD targets. These targets were analyzed via String for protein-to-protein interaction (PPI), followed by identification of hub genes with Cytoscape software. Function enrichment analysis of the hub targets was performed. The interactions between hub targets and corresponding ligands were validated via molecular docking.
Results:
Through screening and analysis, a total of 94 active components and 8 hub targets were identified in the TCM-bioactive compound-hub gene network. Molecular docking results showed that the active components of SMGGD have strong binding affinity for their corresponding targets. According to functional analysis, these hub genes are mainly involved in the TNF, AGE-RAGE, IL-17, and MAPK pathways, which are linked to the host inflammatory response to infection and viral replication. Therefore, SMGGD might suppress the replication of monkeypox virus through the MAPK signaling pathway while also reducing inflammatory damage caused by viral infection.
Conclusion:
SMGGD may have positive therapeutic effects on monkeypox by reducing inflammatory damage and limiting virus replication.
... Flavonoids such as kaempferol are reported to inhibit cation-selective channels formed by the ORF 3a channel of SARS-CoV. As a result, it ultimately inhibits the virus release and stands out as the root of the evolution of new medicinal antiviral drugs [63]. SARS-CoV-2 S-RBD interacts with host receptor ACE-2 via RBD, laying the groundwork for viral entrance in receptor cells [64]. ...
The in silico method has provided a versatile process of developing lead compounds from a large database in a short duration. Therefore, it is imperative to look for vaccinations and medications that can stop the havoc caused by SARS-CoV-2. The spike protein of SARS-CoV-2 is required for the viral entry into the host cells, hence inhibiting the virus from fusing and infecting the host. This study determined the binding interactions of 36 flavonoids along with two FDA-approved drugs against the spike protein receptor-binding domain of SARS-CoV-2 through molecular docking and molecular dynamics (MD) simulations. In addition, the molecular mechanics generalized Born surface area (MM/GBSA) approach was used to calculate the binding-free energy (BFE). Flavonoids were selected based on their in vitro assays on SARS-CoV and SARS-CoV-2. Our pharmacokinetics study revealed that cyanidin showed good drug-likeness, fulfilled Lipinski’s rule of five, and conferred favorable toxicity parameters. Furthermore, MD simulations showed that cyanidin interacts with spike protein and alters the conformation and binding-free energy suited. Finally, an in vitro assay indicated that about 50% reduction in the binding of hACE2 with S1-RBD in the presence of cyanidin-containing red grapes crude extract was achieved at approximately 1.25 mg/mL. Hence, cyanidin may be a promising adjuvant medication for the SARS-CoV-2 spike protein based on in silico and in vitro research.
... Chrysin has anti-oxidant and immunomodulatory properties. Inhibits NFkB pathway as a PPAR γ-agonist, inhibits COX-2, MPO activity, reduces, IL-1β, IL-8, iNOS levels [135][136][137] Kaempferol Inhibition of movement of metabolites through viral 3a ion channels inhibits viral replication [138] Luteolin Binding to Spike protein inhibits viral attachment to host cells, also displays inhibitory activity against SARS-CoV-2 3CL pro. Has anti-oxidant activity, inhibits MAPK, NFκB pathways, reduces COX-2, TNFα, INOS, IL-6,IL-1β, production, and MPO activity [139][140][141][142] Kaempferol, luteolin Kaempferol and luteolin have monoamine oxidase inhibitory activity therapeutic agents in neurodegenerative disorders [143][144][145] Hesperidin/hesperitin Vasodilatory, used to treat stress induced H.pylori gastric ulcer, ulcerative colitis, gastric/mucosal infections. ...
The aim of this review is to highlight the beneficial attributes of flavonoids, a diverse family of widely-distributed polyphenolic phytochemicals that have beneficial cell and tissue protective properties. Phytochemicals are widely distributed in plants, herbs and shrubs used in traditional complimentary medical formulations for centuries. The bioactive components that convey beneficial medicinal effects in these complex herbal preparations are now being identified using network pharmacology and molecular docking procedures that identify their molecular targets. Flavonoids have anti-oxidant, anti-inflammatory, antiviral, antibacterial and anti-cancer properties that have inspired the development of potent multifunctional derivatised flavonoids of improved efficacy. The antiviral properties of flavonoids and the emergence of the severe acute respiratory syndrome (SARS-CoV-2) pandemic has resulted in a resurgence of interest in phytochemicals in the search for efficacious compounds that can prevent viral infection or replication, with many promising plant compounds identified. Promising semi-synthetic flavonoid derivatives have also been developed that inhibit multiple pathological neurodegenerative processes; these offer considerable promise in the treatment of diseases of cognitive decline. Clinical trials are currently being undertaken to evaluate the efficacy of dietary supplements rich in flavonoids for the treatment of virally-mediated diseases. Such trials are expected to identify flavonoids with cell and tissue protective properties that can be harnessed in biomedical applications that may serve as supportive adjunctive procedures to conventional anti-viral drug therapies against diseases such as COVID-19.
... Several flavonoids have an antagonistic impact on SARS-CoV-2. Apigenin, daidzein, luteolin, amentoflavone, epigallocatechin, gallocatechingallate, quercetin, and kaempferol were primarily studied for the inhibition of the proteolytic action of SARS-CoV 3CLpro [20,102,103]. ...
The recent coronavirus disease (COVID-19) outbreak in Wuhan, China, has led to millions of infections and the death of approximately one million people. No targeted therapeutics are currently available, and only a few efficient treatment options are accessible. Many researchers are investigating active compounds from natural plant sources that may inhibit COVID-19 proliferation. Flavonoids are generally present in our diet, as well as traditional medicines and are effective against various diseases. Thus, here, we reviewed the potential of flavonoids against crucial proteins involved in the coronavirus infectious cycle. The fundamentals of coronaviruses, the structures of SARS-CoV-2, and the mechanism of its entry into the host’s body have also been discussed. In silico studies have been successfully employed to study the interaction of flavonoids against COVID-19 Mpro, spike protein PLpro, and other interactive sites for its possible inhibition. Recent studies showed that many flavonoids such as hesperidin, amentoflavone, rutin, diosmin, apiin, and many other flavonoids have a higher affinity with Mpro and lower binding energy than currently used drugs such as hydroxylchloroquine, nelfinavir, ritonavir, and lopinavir. Thus, these compounds can be developed as specific therapeutic agents against COVID-19, but need further in vitro and in vivo studies to validate these compounds and pave the way for drug discovery
... Further, apigenin was documented to depict antiviral effects against the influenza virus, human immunodeficiency virus (HIV), herpes simplex viruses, hepatitis B and C, African swine fever virus, enterovirus 71, Epstein-Barr virus, and foot-and-mouth disease virus [14,18,[58][59][60][61][62][63][64]. Kaempferol previously showed antiviral potential against the SARS-CoV [65], herpes simplex viruses, human immunodeficiency virus or HIV (type 1), and pseudorabies virus [66][67][68]. It is noteworthy that honey also exhibits anti-inflammatory and immunomodulatory activities. ...
COVID-19 caused by SARS-CoV-2 is a serious health crisis worldwide and requires a safe and efficacious treatment to combat the disease. RNA-dependent RNA polymerase (RdRp) and main protease (Mpro) are vital enzymes in the SARS-CoV-2 life cycle and are considered effective drug targets. In the current investigation, fourteen (14) flavonoids from honey were assessed to analyze their potential for RdRp and Mpro inhibition using the computational approach. First, flavonoids were screened based on drug-likeness, which determined all the compounds except epigallocatechin gallate as orally bioavailable drugs with easy absorbance and high permeability. Screened thirteen (13) flavonoids were subjected to molecular docking analysis to identify the potent inhibitors of SARS-CoV-2 target proteins (RdRp and Mpro). The analysis revealed the significant binding affinities of all compounds with both target proteins. Luteolin showed the most stable binding interactions (−7.6 kcal/mol) with the RdRp while apigenin and kaempferol displayed the binding energy of −7.8 kcal/mol with Mpro. Low binding energies and stable interactions indicate these compounds' potential inhibition of target proteins. Toxicity analysis depicted these top compounds as safe drugs while target prediction showed their significant probability of target accuracy in the human body. The findings predict the anti-COVID-19 potential of honey flavonoids as safe drugs where top inhibitor compounds exhibit good pharmacodynamics properties and target accuracy. Further wet-lab experiments involving the in vitro and in vivo assays are recommended to investigate the effectiveness of honey flavonoids to cure the COVID-19.
... In a study of inhibitors against coronavirus, rhoifolin, pectolinarin, herbacetin 45 and amento avone 46 were demonstrated to block the function of SARS-CoV 3CLpro. The glycoside derivatives of kaempferol also proved to be virus release inhibit agents by blocking the 3a channel 47 . During the COVID-19 outbreak, narcissoside 48 and rutin 29 also exhibited the inhibitory effects on main protease of SARS-CoV-2, which is con rmed the practicality of our screening strategy. ...
The current severe situation of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been reversed and posed great threats to global health. Therefore, there is an urgent need to find out effective antiviral drugs. The 3-chymotrypsin-like protease (3CLpro) in SARS-CoV-2 serve as a promising anti-virus target due to its essential role in the regulation of virus reproduction. Here, we report an improved integrated approach to identify effective 3CLpro inhibitors from effective Chinese herbal formulas. With this approach, we identified the 5 natural products (NPs) including narcissoside, kaempferol-3-O-gentiobioside, rutin, vicenin-2 and isoschaftoside as potential anti-SARS-CoV-2 candidates. Subsequent molecular dynamics simulation additionally revealed that these molecules can be tightly bound to 3CLpro and confirmed effectiveness against COVID-19. Moreover, kaempferol-3-o-gentiobioside, vicenin-2 and isoschaftoside were first reported to have SARS-CoV-2 3CLpro inhibitory activity. In summary, this optimized integrated strategy for drug screening can be utilized in the discovery of antiviral drugs to achieve rapid acquisition of drugs with specific effects on antiviral targets.
... Kaempferol has also shown inhibitory activity against human cytomegalovirus [79], as well as against the influenza viruses H1N1 and H9N2 by inhibiting the activity of the viral neuraminidase [80]. A study on kaempferol and other natural derivatives of kaempferol, such as juglanin, afzelin, and tiliroside, showed that they potently inhibited the 3a channel protein of coronavirus [82]. These compounds were also shown to interfere with other steps in the life cycle of viruses [83]. ...
Capparis spinosa L., commonly known as the caper bush, is an aromatic plant growing in most of the Mediterranean basin and some parts of Western Asia. C. spinosa L. has been utilized as a medicinal plant for quite a long time in conventional phytomedicine. Polyphenols and numerous bioactive chemicals extracted from C. spinosa L. display various therapeutic properties that have made this plant a target for further research as a health promoter. This review is meant to systematically summarize the traditional uses, the phytochemical composition of C. spinosa L., and the diverse pharmacological activities, as well as the synthetic routes to derivatives of some identified chemical components for the improvement of biological activities and enhancement of pharmacokinetic profiles. This review also addresses the benefits of C. spinosa L. in adapting to climate change and the socio‐economic value that C. spinosa L. brings to the rural economies of many countries.
... Prenylated flavonoids like Tomentin (A-E) extracted from the fruits of Paulownia tomentosa were reported as competitive inhibitors of SARS-CoV papain-like protease (PLpro) with IC50 ≤ 12.5µM [50]. Other categories of flavonoids like glycosides were mentioned to have an antiviral activity such as Juglanine inhibits ion channel activity of SARS-CoV 3a protein with IC50 of 2.3 μM [51]. Further, Carlino-side from Desmodium styracifolium inhibits ACE activity with IC50 of 33.6 μM [52]. ...
The COVID-19 pandemic has immensely impacted global health causing colossal damage. The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has increased the quest to explore phytochemicals as treatment options. We summarize phytochemicals with activity against various coronaviruses including SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). We compiled 705 phytochemical compounds through text mining of 893 PubMed articles. The physicochemical properties including molecular weight, lipophilicity, and the number of hydrogen bond donors and acceptors were determined from the structures of these compounds. A structure-based evaluation of these properties with respect to drug likeness showed that most compounds have a positive score of drug likeness. QSAR analysis showed that 5 descriptors, namely polar surface area, relative polar surface area, number of hydrogen bond donors, solubility, and lipophilicity, are significantly related to IC50. We envisage that these phytochemicals could be further explored for developing new potential therapeutic molecules for COVID-19.
Supplementary information:
The online version contains supplementary material available at 10.1007/s11224-022-02035-6.
... Dengue disease, a viral disease spread by mosquitoes, occurs in around 390 million cases worldwide every year, where 96 million of those cases lead to severe symptoms (WHO, 2022). Currently, no specific treatment is available for dengue (Schwarz et al., 2014). In recent years, there have been several candidates for targets in the discovery of anti-DENV drugs, including essential proteins such as NS3/NS2B protease, NS3 helicase, E protein, methyltransferase (MTase), and RNA-dependent RNA polymerase (RdRp) of NS5 (Rajapakse et al., 2012). ...
Context: Dengue viruses (DENVs) are the cause of dengue disease, which is one of the most frequent diseases caused by mosquito-borne viral infections. Currently, no specific treatment is available for dengue. Aims: To identify the most promising inhibitors of dengue virus 2 (DENV2) envelope protein of DENV2 envelope protein from flavonoids compounds through computational methods. Methods: Structures of 54 flavonoids were collected, then the compounds were screened based on Lipinski’s rules, and there were only 34 compounds that passed the screening. Then QSAR analysis was performed, followed by molecular docking analysis, ADMET evaluation, and molecular dynamics simulations to assess the stability of the protein. Results: Based on the QSAR analysis, only 32 compounds were subjected to molecular docking analysis. Silymarin had the highest docking score, while juglanin had the lowest ACE score compared to positive controls. The ADMET evaluation showed silymarin and juglanin had good absorption and could not penetrate the blood-brain barrier. In contrast to silymarin which had negative results for the Ames test, carcinogenicity, skin sensitization, and eye irritation, juglanin was positive for Ames test and skin sensitization. Even though the molecular dynamic simulation of both ligands with DENV2 envelope protein showed unstable confirmation, it did not necessarily mean that the ligands cannot be used as inhibitors since the molecular docking results provide evidence of the ligands binding to the DENV2 envelope protein. Conclusions: Based on the favorable results of QSAR analysis, molecular docking, and ADMET evaluation, juglanin and silymarin were chosen as the candidate with the most potential for DENV2 envelope protein inhibitors. However, further analyses such as in vitro and in vivo analyses are necessary to validate the result of this study.
... Yu et al. found in vitro that the flavonoids myricetin and scutellarein can inhibit the SARS-CoV helicase protein [88]. Glycosides of the flavonol kaempferol may be good antiviral agents for 3a channel proteins of coronaviruses [89]. ...
The COVID-19 outbreak seems to be the most dangerous challenge of the third millennium due to its highly contagious nature. Amongst natural molecules for COVID-19 treatment, the flavonoid molecule quercetin (QR) is currently considered one of the most promising. QR is an active agent against SARS and MERS due to its antimicrobial, antiviral, anti-inflammatory, antioxidant, and some other beneficial effects. QR may hold therapeutic potential against SARS-CoV-2 due to its inhibitory effects on several stages of the viral life cycle. In fact, QR inhibits viral entry, absorption, and penetration in the SARS-CoV virus, which might be at least partly explained by the ability of QR and its derivatives to inhibit 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro). QR is a potent immunomodulatory molecule due to its direct modulatory effects on several immune cells, cytokines, and other immune molecules. QR-based nanopreparations possess enhanced bioavailability and solubility in water. In this review, we discuss the prospects for the application of QR as a preventive and treatment agent for COVID-19. Given the multifactorial beneficial action of QR, it can be considered a very valid drug as a preventative, mitigating, and therapeutic agent of COVID-19 infection, especially in synergism with zinc, vitamins C, D, and E, and other polyphenols.
... It may also reduce the expression of TMPRSS2 and inhibit viral attachment to the main ACE2 receptor on human T cells. Crucially, kaempferol also acts on the main protease M pro of the SARS-COV viruses (Schwarz et al. 2014;Solnier and Fladerer 2020) (Fig. 3). ...
This current study review provides a brief review of a natural bee product known as propolis and its relevance toward combat-ing SARS-CoV viruses. Propolis has been utilized in medicinal products for centuries due to its excellent biological properties. These include anti-oxidant, immunomodulatory, anti-inflammatory, anti-viral, anti-fungal, and bactericidal activities. Furthermore, studies on molecular simulations show that flavonoids in propolis may reduce viral replication. While further research is needed to validate this theory, it has been observed that COVID-19 patients receiving propolis show earlier viral clearance, enhanced symptom recovery, quicker discharge from hospitals, and a reduced mortality rate relative to other patients. As a result, it appears that propolis could probably be useful in the treatment of SARS-CoV-2-infected patients. Therefore, this review sought to explore the natural properties of propolis and further evaluated past studies that investigated propolis as an alternative product for the treatment of COVID-19 symptoms. In addition, the review also highlights the possible mode of propolis action as well as molecular simulations of propolis compounds that may interact with the SARS-CoV-2 virus. The activity of propolis compounds in decreasing the impact of COVID-19-related comorbidities, the possible roles of such compounds as COVID-19 vaccine adjuvants, and the use of nutraceuticals in COVID-19 treatment, instead of pharmaceuticals, has also been discussed.
... Flavonoids such as kaempferol are reported to inhibit cation-selective channels formed by the ORF 3a channel of SARS-CoV. As a result, it ultimately inhibits the virus release and stands out as a root of the evolution of new medicinal antiviral drugs [54]. ...
In silico method has provided a versatile process of developing lead compounds from a large database in a short duration. Spike (S) protein of SARS-CoV-2 is required for viral entry into the host cell, hence inhibiting it prevents the virus from fusing and infecting the host. This study determined the binding interaction of 36 flavonoids against the S protein receptor-binding domain (RBD) of SARS-CoV-2 through molecular docking and molecular dynamics (MD) simulation. In addition, the molecular mechanics generalized Born surface area (MM/GBSA) approach was used to calculate the binding free energy (BFE). Flavonoids were selected based on their in vitro assays on SARS-CoV and SARS-CoV-2, respectively.
... Quercetin 3-rutinoside-7-glucoside is a flavonoid glycoside identified in W. somnifera aerial part (Mundkinajeddu et al. 2014). Antiviral potential of flavonoid glycoside has been reported against human coronaviruses (Schwarz et al. 2014). Furthermore, chlorogenic acid, isochlorogenic acid B, caffeoyl-quinic acid, sitoindosite X, and 4-2-3-didehydrosomnifericin phytochemicals showed better binding efficacy than respective standard inhibitors of the targeted proteins (Tables 1 and 2). ...
Coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has infected approximately 26 million people and caused more than 6 million deaths globally. Spike (S)-protein on the outer surface of the virus uses human trans-membrane serine protease-2 (TMPRSS2) to gain entry into the cell. Recent reports indicate that human dipeptidyl peptidase-4 inhibitors (DPP4 or CD26) could also be utilized to check the S-protein mediated viral entry into COVID-19 patients. RNA dependent RNA polymerase (RdRp) is another key virulence protein of SARS-CoV-2 life cycle. The study aimed to identify the potential anti-SARS-CoV-2 inhibitors present in Withania somnifera (Solanaceae) using computer aided drug discovery approach. Molecular docking results showed that flavone glycoside, sugar alcohol, and flavonoid present in W. somnifera showed - 11.69, - 11.61, - 10.1, - 7.71 kcal/mole binding potential against S-protein, CD26, RdRp, and TMPRSS2 proteins. The major standard inhibitors of the targeted proteins (Sitagliptin, VE607, Camostat mesylate, and Remdesivir) showed the - 7.181, - 6.6, - 5.146, and - 7.56 kcal/mole binding potential. Furthermore, the lead phytochemicals and standard inhibitors bound and non-bound RdRp and TMPRSS2 proteins were subjected to molecular dynamics (MD) simulation to study the complex stability and change in protein conformation. The result showed energetically favorable and stable complex formation in terms of RMSD, RMSF, SASA, Rg, and hydrogen bond formation. Drug likeness and physiochemical properties of the test compounds exhibited satisfactory results. Taken together, the present study suggests the presence of potential anti-SARS-CoV-2 phytochemicals in W. somnifera that requires further validation in in vitro and in vivo studies.
Graphical abstract:
Supplementary information:
The online version contains supplementary material available at 10.1007/s42535-022-00404-4.
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
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.
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.
Background:
Two important flavonoids, kaempferol and quercetin possess remarkably potent biological impacts on human health. However, their structural complexity and low abundance in nature make both bulk chemical synthesis and extraction from native plants difficult. Therefore microbial production via heterologous expression of plant enzymes can be a safe and sustainable route for their production. Despite several attempts reported in microbial hosts, the production levels of kaempferol and quercetin still stay far behind compared to many other microbial-produced flavonoids.
Results:
In this study, Saccharomyces cerevisiae was engineered for high production of kaempferol and quercetin in minimal media from glucose. First, the kaempferol biosynthetic pathway was reconstructed via screening various F3H and FLS enzymes. In addition, we demonstrated that amplification of the rate-limiting enzyme AtFLS could reduce the dihydrokaempferol accumulation and improve kaempferol production. Increasing the availability of precursor malonyl-CoA further improved the production of kaempferol and quercetin. Furthermore, the highest amount of 956 mg L- 1 of kaempferol and 930 mg L- 1 of quercetin in yeast was reached in fed-batch fermentations.
Conclusions:
De novo biosynthesis of kaempferol and quercetin in yeast was improved through increasing the upstream naringenin biosynthesis and debugging the flux-limiting enzymes together with fed-batch fermentations, up to gram per liter level. Our work provides a promising platform for sustainable and scalable production of kaempferol, quercetin and compounds derived thereof.
Background and aim:
Feline infectious peritonitis (FIP), one of the most important infectious diseases in cats is caused by FIP virus (FIPV), a mutated variant of feline coronavirus. Feline infectious peritonitis has a negative impact on feline health, with extremely high mortality in clinical FIP-infected cats, particularly young cats. There are no approved drugs for FIP treatment, and therapeutic possibilities for FIP treatment are limited. This study aimed to utilize nature-derived bioactive flavonoids with antiviral properties to inhibit FIPV infection in Crandell-Rees feline kidney (CRFK) cells.
Materials and methods:
The cytotoxicity of 16 flavonoids was evaluated on CRFK cells using a colorimetric method (MTS) assay. Viral kinetics of FIPV at 50 tissue culture infectious dose (TCID50)/well was determined during the first 24-h post-infection (HPI). Antiviral activity was evaluated based on the replication steps of the virus life cycle, including pre-compound, attachment, penetration, post-viral entry, and virucidal assays. The antiviral efficacy of flavonoids against FIPV was determined based on positive FIPV-infected cells with the immunoperoxidase monolayer assay and viral load quantification using reverse transcription-quantitative polymerase chain reaction.
Results:
Two flavonoids, namely, isoginkgetin and luteolin, inhibited FIPV replication during post-viral entry in a dose-dependent manner, with 50% maximal effective concentrations = 4.77 ± 0.09 and 36.28 ± 0.03 μM, respectively. Based on viral kinetics, both flavonoids could inhibit FIPV replication at the early stage of infection at 0-6-HPI for isoginkgetin and 2-6-HPI for luteolin using a time-of-addition assay. Isoginkgetin exerted a direct virucidal effect that reduced the viral titers by 2 and 1.89 log10 TCID50/mL at 60 and 120 min, respectively.
Conclusion:
Isoginkgetin interfered with FIPV replication during both post-viral infection and virucidal experiments on CRFK cells, whereas luteolin inhibited the virus after infection. These results demonstrate the potential of herbal medicine for treating FIP.
Background
The rapid global spread of the COVID-19 pandemic urged scientists to search for effective and safe anti-coronavirus drugs from natural resources. Through centuries, traditional medicinal plants have been providing cure for diseases and general health care worldwide.
Objective
The main aim of this review was to explore and summarize the research works on the different plants used traditionally in Sudan to treat signs and symptoms of COVID-19 and respiratory diseases, characterizing their antiviral activities and exploring the different phytochemicals present in these plants.
Method
The current review was carried out in line with the recommendations of the PRISMA 2020 statement. Information on plants traditionally used in Sudan to treat the signs and symptoms of COVID-19 and respiratory diseases was obtained from traditional medicine books and published articles, as well as the daily practice by ordinary people.
Results
This article illustrated the use of 27 plant species belonging to 15 families in Sudanese traditional medicine to treat signs and symptoms of COVID-19 and respiratory diseases. Leguminosae/Fabaceae was found to be the most represented family (7 species), followed by Combretaceae (3 species) and Capparidaceae and Malvaceae (2 species each). From these plants, about 11 plant species were studied for their antiviral activity against at least one virus, and 5 plants, namely Adansonia digitata, Boscia senegalensis, Hibiscus sabdariffa, Nigella sativa, and Mangifera indica, were tested for their antiviral activity against influenza viruses. The phytoconstituents of the listed plants were summarized, and the antiviral activity of their isolated bioactive compounds was highlighted.
Conclusion
The review could provide an in-depth theoretical basis and valuable data for designing future studies.
Public health is still under attack by a worldwide pandemic caused by a coronavirus which is known to cause mainly respiratory and enteric disease in humans. Currently, still limited knowledge exists on the exact action mechanism and biology of SARS‒CoV‒2 although there are several effective vaccines and antiviral treatment. Besides, there is a considerable amount of 3D protein structures for SARS–CoV–2, related to its main protease resolved by X–ray diffraction. Here, we used molecular docking strategy to predict possible inhibitory activities of flavonoids on SARS–CoV–2 Mpro enzyme. For this, 800 flavonoids were retrieved from the ZINC database. Results suggested that avicularin was the lead flavonoid which docked to Mpro with the best binding energy. However, most of flavonoids showed H–bond interactions with Hie–41 and Cys–145 catalytic dyad, which were important residues for the catalytic activity of SARS–CoV–2 Mpro. Strong hydrogen bonding (2.36 Å) with Sγ atom of Cys145 residue was observed. This might suggest an initial formation of covalent bonding. Findings showed that selected flavonoids could be promising inhibitors of this enzyme and have the potential for future therapeutic drugs against COVID–19 after immediate experimental validation and clinical approvals.
Background
Indian traditional medicinal plants are known for their great potential in tackling viral diseases. Previously, we reported a systematic review approach of seven plausible traditional Indian medicinal plants against SARS CoV 2.
Methods
Molecular docking was conducted with Biovia Discovery Studio. Three binding domains for Spike glycoprotein (PDB IDs: 6LZG, 6M17, 6M0J) and one binding domain of RdRp (PDB ID: 7BTF) were used. Among 100 phytoconstituents listed from seven plants by IMPPAT Database used for virtual screening, the best six compounds were again filtered using Swiss ADME prediction and Lipinski's rule. Additionally, a Pseudovirion assay was performed to study the interaction of SARS CoV 2 S1-protein with the ACE 2 receptor for further confirming the effect.
Results
Chebulagic acid (52.06 Kcal/mol) and Kaempferol (48.84 Kcal/mol) showed an increased interaction energy compared to Umifenovir (33.68 Kcal/mol) for the 6LZG binding domain of Spike glycoprotein. Epicatechin gallate (36.95 Kcal/mol) and Arachidic acid (26.09 Kcal/mol) showed equally comparable interaction energy compared to Umifenovir (38.20 Kcal/mol) for 6M17 binding domain of Spike glycoprotein. Trihydroxychalcone (35.23 Kcal/mol) and Kaempferol (36.96 Kcal/mol) showed equally comparable interaction energy with Umifenovir (36.60 Kcal/mol) for 6M0J binding domain of Spike glycoprotein. On analyzing the phytoconstituents against RdRp binding domain, DL-Arginine (41.78 Kcal/mol) showed comparable results with the positive control Remdesivir (47.61 Kcal/mol). ADME analysis performed using Swiss ADME revealed that Kaempferol and DL Arginine show drug-like properties with appropriate pharmacokinetic parameters. Further in vitro analysis of Kaempferol by Pseudo virion assay confirmed an acceptable decrease of the lentiviral particles on transfected HEK293T-hACE2 cells.
Conclusion
The study highlights that Kaempferol and DL-Arginine could be the significant molecules to exhibit potent action against SARS CoV 2 and its variants.
Eugenia pyriformis Cambess (Myrtaceae), conhecida popularmente como uvaia. Em seus frutos são encontrados compostos fenólicos com ação antioxidante e nas folhas foram detectados altos teores de flavonoides e taninos hidrolisados que se mostraram inibidor da protease de 2019 - nCoV e SARS-CoV. Neste sentido, o objetivo deste estudo foi a obtenção do extrato bruto das folhas, a análise da composição química e a possibilidade da ação antiviral frente ao SARS COV-2. O extrato bruto (EB) foi obtido a partir das folhas secas de E. pyriformis, pela técnica de maceração dinâmica com esgotamento do solvente (etanol 90º GL) e concentrado em evaporador rotativo. Seis gramas do EB foram fracionados em cromatografia em coluna, e eluído com hexano, diclorometano, acetato de etila e metanol, as frações foram concentradas em um evaporador rotativo (Tecnal TE-210). O EB e as frações foram identificadas por cromatografia líquida de alta eficiência à espectrometria de massas de alta resolução (CLAE-ESI/qTOF). A identificação química do extrato bruto e frações das folhas de E. pyriformis evidenciou a presença de compostos fenólicos destacando os ácidos fenólicos, flavonoides e taninos. De forma complementar, foi realizado um levantamento bibliográfico sobre a provável ação antiviral dos compostos fenólicos e taninos presentes nas folhas de uvaia. Os resultados evidenciaram que os flavonoides quercetina e kaempferol possuem ação antiviral quando se ligam a glicoproteína do envelope ou capsídeo viral interferindo na ligação e penetração do vírus na célula. Este resultado coloca as folhas de E. pyriformis na lista de plantas com ação antiviral.
Plant Bioactives as Natural Antivirals: A Concise Review
Abstract: The current century has witnessed infections of pandemic proportions caused by Coron�aviruses (CoV) including severe acute respiratory syndrome-related CoV (SARS-CoV), Middle East respiratory syndrome-related CoV (MERS-CoV) and the recently identified SARS-CoV2. Significantly, the SARS-CoV2 outbreak, declared a pandemic in early 2020, has wreaked devastation and imposed intense pressure on medical establishments world-wide in a short time period by spreading at a rapid pace, resulting in high morbidity and mortality. Therefore, there is a compelling need to combat and contain the CoV infections. The current review addresses the unique features of the molecular virology of major Coronaviruses that may be tractable towards antiviral targeting and design of novel preventative and therapeutic intervention strategies. Plant-derived vaccines, in particular oral vaccines, afford safer, effectual and low-cost avenues to develop antivirals and fast response vaccines, requiring minimal infrastructure and trained personnel for vaccine administration in developing countries. This review article discusses recent developments in the generation of plant-based vaccines, therapeutic/drug molecules, monoclonal antibodies and phytochemicals to preclude and combat
infections caused by SARS-CoV, MERS-CoV and SARS-CoV-2 viruses. Efficacious plant-derived antivirals could contribute significantly to combating emerging and re-emerging pathogenic CoV infections and help stem the tide of any future pandemics.
Coronavirus disease 2019 (COVID-19) is a pandemic that has devastated the world, causing the deaths of tens of thousands people. This disease is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). So far, no vaccine or treatment could be properly developed. This chapter examined all the works that have reported experimental results on the treatment of SARS-CoV and SARS-CoV-2 infections using natural bioactive molecules. Findings were presented in a very clear and detailed way based on the relationship that exists between successful applications of these natural drugs against the two SARS coronaviruses. Scutettaria baicalensis, Urtica dioica, Psoralea corylifolia, Radix Polygoni multiflori, Allium sativum L., and Nigella sativa are promising plants for the treatment of COVID-19. The two herbal formulas Lianhuaqingwen and Qingfei Paidu have also attracted interests. Other plants containing lectins, flavonoids, baicalin, scutellarein, myricetin, and herbacetin can be considered as potential source of bioactives for drug discovery and treatments.
Background
Coronavirus disease 2019 (COVID‑19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and is associated with a high level of mortality.
Objective
This updated review aims to present the most important traditional medicinal plants and some of their secondary metabolites that have previously and more recently been shown to affect viruses and may represent a beneficial contributory step against SARS-CoV-2 as the cause of COVID-19. Moreover, the mechanism aspects of these secondary metabolites were discussed, which may help find more reliable drugs against SARS-CoV-2.
Methods
Articles were searched in scientific websites including Google Scholar, Scopus, Web of Science, PubMed, and IranMedex using the search terms herbal medicine and traditional medicine with coronavirus, SARS-CoV-2, or COVID-19. Human, animal, and in vitro studies were identified in the search.
Results
Medicinal plants and their secondary metabolites may possess a potential role in combating this disease, and researchers suggest that some of these plants and their constituent compounds have inhibitory activity on coronaviruses. Numerous medicinal plants, their extracts, and secondary metabolites have been investigated over a period of time for antiviral activity. Among them, kaempferol, silybin, myricitrin, licoleafol, and curcumin are promising agents with potential activity against SARS-CoV-2. Natural compounds can form strong bonds with the active sites of SARS-CoV-2 protease. Structural and non-structural SARS-CoV-2 proteins such as Spike protein, PLpro, and 3CLpro are inhibited by these phytochemicals.
Conclusion
Prospective treatments targeted at the life cycle stages of the virus may eventuate from research endeavors, and it must not be discounted that therapy originally derived from plant secondary metabolite sources may potentially have a part to play.
The current coronavirus disease (COVID-19) outbreak is a significant threat to human health and the worldwide economy. Coronaviruses cause a variety of diseases, such as pneumonia-like upper respiratory tract illnesses, gastroenteritis, encephalitis, multiple organ failure involving lungs and kidneys which might cause death. Since the pandemic started there have been more than 107 million COVID-19 infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ∼2.4 million deaths globally. SARS-CoV-2 is easily transmitted from person-to-person and has spread quickly across all continents. With the continued increase in morbidity and mortality caused by COVID-19, and the damage to the global economy, there is an urgent need for effective prevention and treatment strategies. The advent of safe and effective vaccines has been a significant step forward in the battle against COVID-19, however treatment of the symptoms associated with the disease still requires new anti-viral and anti-inflammatory drug therapies. To this end, scientists have been investigating available natural products that may be effective against SARS-CoV-2, with some products showing promise in fighting several viral infections. Since many natural products are dietary components or are prepared as dietary supplements people tend to consider them safer than synthetic drugs. For example, Traditional Chinese Medicines have been effectively utilized to treat SARS-CoV-2 infected patients with promising results. In this review, we summarize the current knowledge of COVID-19 therapies and the therapeutic potential of medicinal plant extracts and natural compounds for the treatment of several viral infections, with special emphasis on SARS-CoV-2 infection. Realistic strategies that can be employed for the effective use of bioactive compounds for anti-SARS-CoV-2 research are also provided.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a substantial number of deaths around the world, making it a serious and pressing public health hazard. Phytochemicals could thus provide a rich source of potent and safer anti-SARS-CoV-2 drugs. The absence of approved treatments or vaccinations continues to be an issue, forcing the creation of new medicines. Computer-aided drug design has helped to speed up the drug research and development process by decreasing costs and time. Natural compounds like terpenoids, alkaloids, polyphenols, and flavonoid derivatives have a perfect impact against viral replication and facilitate future studies in novel drug discovery. This would be more effective if collaboration took place between governments, researchers, clinicians, and traditional medicine practitioners’ safe and effective therapeutic research. Through a computational approach, this study aims to contribute to the development of effective treatment methods by examining the mechanisms relating to the binding and subsequent inhibition of SARS-CoV-2 ribonucleic acid (RNA)-dependent RNA polymerase (RdRp). The in silico method has also been employed to determine the most effective drug among the mentioned compound and their aquatic, nonaquatic, and pharmacokinetics’ data have been analyzed. The highest binding energy has been reported -11.4 kcal/mol against SARS-CoV-2 main protease (7MBG) in L05. Besides, all the ligands are noncarcinogenic, excluding L04, and have good water solubility and no AMES toxicity. The discovery of preclinical drug candidate molecules and the structural elucidation of pharmacological therapeutic targets have expedited both structure-based and ligand based drug design. This review article will assist physicians and researchers in realizing the enormous potential of computer-aided drug design in the design and discovery of therapeutic molecules, and hence in the treatment of deadly diseases.
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.