Plant-Derived Epi-Nutraceuticals as Potential Broad-Spectrum Anti-Viral Agents: Comparison
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Please note this is a comparison between Version 3 by Lindsay Dong and Version 5 by Jamal Mahajna.

Plant-derived products, which have been used in traditional medicine for treating pathological conditions, offer structurally novel therapeutic compounds, including those with anti-viral activity. In addition, plant-derived bioactive substances might serve as the ideal basis for developing sustainable/efficient/cost-effective anti-viral alternatives. Interest in herbal antiviral products has increased. More than 50% of approved drugs originate from herbal sources. Plant-derived compounds offer diverse structures and bioactive molecules that are candidates for new drug development. Combining these therapies with conventional drugs could improve patient outcomes. Epigenetics modifications in the genome can affect gene expression without altering DNA sequences. Host cells can use epigenetic gene regulation as a mechanism to silence incoming viral DNA molecules, while viruses recruit cellular epitranscriptomic (covalent modifications of RNAs) modifiers to increase the translational efficiency and transcript stability of viral transcripts to enhance viral gene expression and replication. 

  • plant-derived substances
  • epigenetic modifications
  • virus
  • broad-spectrum anti-viral

1. Introduction

Although vaccines are used to combat certain viruses, antiviral therapy is still a common approach [1]. Interest in herbal products with antiviral activity has increased significantly, and in recent years, more than 50% of approved antiviral drugs have been produced from herbal sources [2][3]. Indeed, they are particularly rich in compounds with great structural diversity.
Plant-derived compounds offer a wide range of chemical structures and bioactive molecules, increasing the likelihood of discovering novel antiviral compounds. This approach is consistent with the increasing importance of sustainable and environmentally friendly drug discovery and development. Plant-derived compounds can exhibit a broad spectrum of activity, reduce drug resistance, and provide a multi-target approach that increases the efficacy of antiviral therapies. Combining these therapies with conventional antiviral drugs could lead to synergistic effects and improved treatment outcomes. However, extensive preclinical and clinical studies are still needed to determine the safety and efficacy of plant-based epigenetic modulators as antiviral therapies. Plant-derived products are mainly essential oils (EOs), extracts, and isolated compounds that have been extensively studied for their antiviral properties against different viral strains [4][5].
EOs and extracts from different plant families such as Lamiaceae, Myrtaceae, Asteraceae, Brassicaceae, Rutaceae, Apiaceae, and Geraniaceae were found to be highly effective. Among them, the essential oils of Illicium verum Hooker f. and Rosmarinus officinalis L. were extremely effective against herpes simplex virus-1 (HSV-1) with IC50 values of 1 and 0.18 µg/mL, respectively [6][7]. In addition, Cymbopogon citratus (DC.) Stapf, Cananga odorata (Lam.) Hook.f. & Thomson, and C. nardus (L.) Rendle showed great efficacy against HIV with IC50 values of 0.61, 0.60, and 1.2 µg/mL, respectively [8][9]. Finally, Eucalyptus globulus Labill. proved to be highly effective against Coxsackie virus B3 with an IC50 of 0.7 µg/mL.
Herbal EOs and extracts are more effective than pure isolated compounds in some cases. EOs are usually complex mixtures of volatile secondary metabolites such as terpenes, alcohols, ethers, aldehydes, ketones, or esters. The extracts are also complex mixtures of organic compounds that are extracted depending on the polarity and solvent used. Consequently, the activity of EOs and extracts is not due to a single component but may be associated with the synergistic action of two or more components with antiviral activity.
Herbal products exert their antiviral activity with different modes of action. They may inhibit virus attachment, penetration, and entry into the host cell or inhibit other intercellular cell signaling pathways [10]. Other modes of action include the disruption of the viral life cycle or inhibition of other essential enzymes for viral reproduction [11].
A wide range of compounds are found in plants and their extracts, some of which have been isolated and tested to identify the main contributors to antiviral activity. Most of them belong to the classes of polyphenols, terpenes, or alkaloids. In some cases, the compounds have shown strong potential against several viruses.
Among the terpenes, raoulic acid purified from Raoulia australis Hook. F. purified extract showed antiviral activity against five virus strains, i.e., human rhinoviruses serotype 2 (HRV2), human rhinoviruses serotype 23 (HRV3), coxsackievirus B3 (CB3), coxsackievirus B4 (CB4), HRV3, CB3, CB4, and Enterovirus 71 (EV71) (IC50 values of <0.1, 0.19, 0.33, 0.40, and <0.1 µg/mL, respectively) [12]. In addition, farnesol, β-eudesmol, and carvacrol showed great potency against HSV-1 with IC50 values of 0.25, 3.5, and 6 μg/mL, respectively [6]. The classes of polyphenols and flavonoids contain the most compounds with antiviral activity. For example, chebulagic acid, a tannin derived from Terminalia chebula Retz, was effective against viruses that use glycosaminoglycans for entry such as human Cytomegalovirus (HCMV), hepatitis C virus (HCV), Dengue virus 2 (DENV-2), HCV, DENV-2, and respiratory syncytial virus (RSV)RSV, showing IC50 values of 25.50, 12.16, 13.11, and 0.38 µM, respectively [13]. Baicalein, belonging to the flavonoid class, potently suppressed HCMV and HSV1, and the IC50 were determined to be 2.2 and 5 µM, respectively [14][15].
Finally, alkaloids, which are small nitrogen-containing molecules, have a molecular basis of specificity and the ability to act on multiple viruses with different mechanisms of action [2]. Among them, tetrandrine and cepharanthine showed strong potential against HcOV (IC50 values of 0.33 μM and 0.83 μM, respectively), while berberine was effective against HCMV, HSV1, and HSV2 (IC50 values of 2.65, 6.77, and 5.04 μM, respectively) [16][17][18].

2. Plant-Derived Epi-Nutraceuticals as Potential Broad-Spectrum Anti-Viral Agents

2.1. Andrographolide

Andrographolide (AGL), has been used in traditional medicine for millennia to cure a range of diseases, such as colds, flu, and malaria [19][20]. AGL contains many substances that have an antiviral effect [19][20]. AGL inhibited human immunodeficiency viruses (HIV), HSV-1, hepatitis B virus (HBV)HBV, HCV, Zika virus (ZIKV)IKV, Chikungunya virus (CHIKV), and Influenza A virus (IAV)IAV [21]. AGL and its analogues reduce ZIKV and DENV infections and have been linked to a decrease in HSPA1A expression and an increase in Phosphoglycerate Kinase 1 (PGK1)GK1 protein expression [22]. Foot-and-mouth disease (FMD) is caused by the FMD virus (FMDV) and has a detrimental impact on livestock all over the world. FMDV was suppressed by AGL in BHK-21 cells. AGL reduced FMDV 3Cpro activity as monitored in an intracellular protease assay. Furthermore, AGL greatly inhibited the 3Cpro’s interferon (IFN) antagonistic effect by inhibiting the expression of interferon-stimulating genes (ISGs) [23]. AGL prevents Epstein–Barr virus (EBV)V reactivation in EBV-positive cancer cells by suppressing EBV lytic genes, most likely via histone modifications such as H3-K9 modification and H3-K27 methylation [24]. AGL has been shown to prevent infections of DENV [22], ZIKV, and other arboviruses [25]. AGL and its derivative showed significant activity against IAV including the H5N1 avian IVA both in vitro and in vivo [26].
AP has shown promising results in treating liver diseases, including viral hepatitis, liver injury, liver fibrosis, fatty liver, and liver cancer. However, clinical applications of AP are rare due to its poor solubility and low bioavailability. AP activity mediated the modulation of miRNA. Specifically, MiR-377, which controls heme oxygenase-1 (HO-1), was significantly decreased by AP-induced nuclear factor erythroid 2-related factor 2 (Nrf2) activity. In addition, AP downregulates miR-433 which modulates the glutathione cysteine ligase. On the other hand, AP upregulates miR-17 and miR-224 which regulate the expression of thioredoxin. Moreover, AP upregulates miR-181a which regulates glutathione peroxidase [27].

2.2. Apigenin

Apigenin (4′,5,7-trihydroxyflavone) is a flavone found in a variety of plants, including medicinal plants [28]. Apigenin displayed a potent histone deacetylases (HDAC) inhibitor activity in human prostate cancer PC-3 cells, specifically decreasing HDAC1 and HDAC3 activity [29]. It also increased the global acetylation of histones H3 and H4 and directed histone H3 hyperacetylation to the p21/WAF1 promoter [29]. Furthermore, molecular studies revealed that apigenin enhances acetylated H3, particularly in the p21WAF1/CIP1 promoter region, leading to upregulating p21WAF1/CIP1 transcription [30]. Apigenin exhibited antiviral properties against IAV, human rhinovirus (HRV), HSV, enterovirus, HBV, HCV, EV71, and SARS-CoV-2 [31][32][33][34]. Its anti-viral activity is attributed, in part, to the inhibition of HDAC activity and chromatin remodeling [29][35]. Apigenin, linalool, and ursolic acid showed a strong anti-viral activity towards coxsackievirus B1 (CVB1) [36]. 

2.3. Baicalein

Baicalein is a flavonoid derived from the roots of Scutellaria baicalensis Georgi., a traditional Chinese medicinal herb [37]. It has been investigated for its anti-viral properties against a variety of viruses, including HBV [38], HIV [39], DENV [40], and HSV-1 [41]. Baicalein was reported to inhibit DNA methyltransferases (DNMT) and HDAC and thereby influence epigenetic modifications [42][43]. Baicalein inhibited HDAC-1/8, causing growth suppression and differentiation induction in acute myeloid leukemia (AML) cell lines. Baicalein might activate HDAC-1 degradation mediated by the ubiquitin-proteasome pathway, thereby increasing histone H3 acetylation [42].

2.4. Berberine

Berberine (BBR) is a quaternary ammonium salt of the protoberberine group of benzylisoquinoline alkaloids found in plants such as Berberis vulgaris L. [44], which exhibited anticancer activity by affecting epigenetic regulation and AMP-activated protein kinase (AMPK) activation [45]. Berberine has exceptional anticancer effects via affecting the enzyme involved in histone acetylation and methylation in acute myeloid leukemia (AML) cell lines [46] and the suppression of Sirtuin 1 (SIRT1) deacetylases in a p53-dependent manner [47]. Berberine inhibited miR-21 expression and promoted integrin β4 (ITGβ4) and programmed cell death 4 (PDCD4) protein expression in colon cancer cell lines. The overexpression of miR-21 reduced the anti-cancer effects of berberine on cancer cells [48]. BBR was reported to influence multiple biological activities, including anticancer, anti-inflammatory, and anti-viral activities [49]. BBR targets multiple steps of the viral life cycle, rendering it an excellent candidate for use in innovative anti-viral drugs and therapies. BBR was discovered to inhibit viral replication by targeting specific interactions between a virus and its host. BBR binds to DNA, inhibiting DNA synthesis and reverse transcriptase activity. It was shown to inhibit the replication of HSV [50], HCMV [51], human papillomavirus (HPV) [52], DENV [53], HIV [54], HCV [55], and SARS-CoV-2 [56]. BBR exhibited anti-viral effects on IAV both in vitro and in vivo [57]. BBR possesses the ability to control the Mitogen-activated protein kinase(MEK)/extracellular-signal-regulated kinase (ERK)EK-ERK, AMPK/mammalian target of rapamycin (mTOR), and nuclear factor kappa B (NF-κB)NF-κB signaling pathways, which are all necessary for viral replication. Protein phosphorylation is crucial in the infection cycle of many viruses [58], affecting cellular protein’s stability, activity, interaction with other proteins, and infectivity. Viruses like EBV [59], HCV [59], SARS-CoV-2, DENV [60], and others [61][62][63], rely on MAPK p38 for replication, suggesting that MAPK p38 inhibitors may exhibit broad-spectrum anti-viral activity. Varghese et al. discovered that BBR significantly reduces MAPK activity. The p38 mitogen-activated protein kinases (p38), extracellular signal-regulated kinases (ERK), and JNK signaling pathways are all significantly blocked by BBR, which specifically targets the ERK signaling pathway, resulting in a significant decrease in virion production. The reduction in viral protein expression following BBR treatment is most likely due to a decrease in virus-induced signaling. BBR treatment has no effect on virus entry or viral replicas’ enzymatic activity [64]. Additionally, it has been shown that BBR has the ability to suppress p38 MAPK activity in the context of HBV infection. The virion of HBV comprises a genome consisting of partially double-stranded relaxed circular DNA (rcDNA). Upon infecting a cell, this rcDNA is transformed into covalently closed circular DNA (cccDNA) in the nucleus. MAPK p38 activity plays a crucial role in the preservation of HBV covalently closed circular DNA (cccDNA) within infected cells [65]. The cccDNA functions as a molecular scaffold for the transcription of RNA molecules, such as mRNAs and pregenomic RNAs (pgRNAs).

2.5. Betulinic Acid

Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid found in the bark of various plant species, most notably the white birch (Betula pubescens Ehrh.) [66]. BA is capable of inducing apoptosis in tumor cells by directly activating the mitochondrial apoptosis pathway via a p53- and CD95-independent mechanism [67]. A computational approach demonstrated that BA has the capacity to alter HDAC6 and HDAC10 activities [68]. Furthermore, BA exhibited an anti-cancer activity that is mediated through cannabinoid receptors (CBs). BA functions as both a CB1 antagonist and a CB2 agonist [69]. BA was used for the treatment of various viral diseases [70]. BA has demonstrated activity in inhibiting DENV-2 NS5 polymerase [71]. Furthermore, BA exhibited an inhibitory effect on HBV replication [72]. Interestingly, the C-3 esterification of BA led to the discovery of Bevirimat, an HIV-1 maturation inhibitor patented by Sanofi-Aventis.

2.6. Butyric Acid

Butyric acid is a fatty acid derived from multiple vegetable sources that have anticancer activity through several pathways, including its influence on epigenetic machineries. Butyrate, alone or in combination with other drugs, including nicotinamide (NA), was shown to have anticancer activity in vivo [73]. Butyric acid exerts its anti-tumor effect by increasing HDAC expression and activity, which is accompanied by an upregulation of miR-203 promoter methylation [73]. Butyrate inhibited HBV replication and cell proliferation by inhibiting SIRT-1 expression in hepatoma cells. Specifically, butyrate inhibited HBx protein expression, HBV-DNA, and hepatitis B surface antigen (HBsAg) [74].

2.7. Cardamonin

Cardamonin (CDN) is a natural chalcone isolated from the seeds of Alpinia katsumadai Hayata [75]. CDN has been shown to have a variety of pharmacological activities, including anticancer and anti-inflammatory properties [76]. It was recently revealed that CDN has anti-viral activity against the human coronavirus HCoV-OC43. CDN exhibits significant efficacy in reducing HCoV-OC43-induced cytopathic effects. CDN suppressed HCoV-OC43 infection by promoting the p38 MAPK signaling pathway and having therapeutic potential against other human coronaviruses [76].

2.8. Cordycepin

Cordycepin is a nucleotide analog derived from Cordyceps mushrooms [77]. In SNU719 cells, cordycepin treatment enhanced BAF chromatin remodeling complex subunit 7A (BCL7A) methylation while suppressing demethylation [78]. Cordycepin promoted methylation at EBV genomic sites near its Fp/Qp promoters. These findings indicate that cordycepin enhances DNMT3 activation, hence increasing the methylation of both genomic and EBV DNA loci in SNU719 cells [78], causing reduced EBV replication [79]. Cordycepin was also shown to have anti-SARS-CoV-2 replication activity [79]. Cordycepin shows anti-viral activities that are attributable to its ability to inhibit several protein kinases [77]. Cordycepin, an adenosine derivative, differs from adenosine in that its ribose lacks an oxygen atom in the 3′ position [80].

2.9. Corosolic Acid

Corosolic acid (CA) is a triterpene acid isolated from Lagerstroemia speciose L. [81]. This bioactive molecule is prevalent in foods such as guava, loquat, and olive, and has anti-inflammatory, anti-metabolic syndrome, and anti-neoplasic properties [82]. CA is implicated in the regulation of DNA methylation and histone H3 methylation. CA modulates CpG methylation sites, resulting in altered gene expression in treated cells [83]. Furthermore, CA inhibits the production and activity of epigenetic modulatory proteins, suggesting its capacity to prevent prostate carcinogenesis [84].

2.10. Curcumin

Curcumin, the major bioactive in turmeric, is a polyphenol with anti-inflammatory and anti-cancer activities [85]. Curcumin has been demonstrated to be a powerful epigenetic regulator with multiple effects on HDAC expression and activity. Curcumin decreased the expression of HDAC1, HDAC3, and HDAC8 proteins, as well as histone acetyltransferase p300, while enhancing the acetylation of Ac-histone H4 protein [86]. Curcumin was shown to reduce HAT activity and has been proposed as a potential DNMT and HDAC inhibitor [87]. Curcumin reduced the amount of HBsAg and the number of cccDNA copies, resulting in the inhibition of HBV replication, which was accompanied by a decrease in the acetylation level of cccDNA-bound histone H3 and H4 [88]. An MiRNA array revealed that miR-350, miR-17-2-3p, let 7e-3p, miR-1224, miR-466b-1-3p, miR-18a-5p, and miR-322-5p were downregulated by curcumin while miR-122-5p, miR-3473, miR-182, and miR-344a-3p were upregulated [89]. Overall, the curcumin-modified miRNAs had an impact on a number of signaling pathways, such as Wnt, NK-κB, MAPK, inflammatory response genes, and viral transmission [90].

2.11. Ellagic Acid

Ellagic acid (EA) is a ubiquitous phenolic molecule isolated from a variety of fruits and vegetables and is well known for its anti-cancer effect [91]. This bioactive substance has been demonstrated to effectively induce HDAC activity. Human adipogenic stem cells treated with EA showed a substantial increase in HDACs’ gene expression. EA also suppresses adipocyte differentiation through coactivator-associated arginine methyltransferase 1 (CARM1)-mediated chromatin modification. This compound also inhibited adipocyte growth and differentiation by increasing histone arginine methylation [92], resulting in an increase in acetylated histone through epigenetic alterations mediated by coactivator-associated CARM1 inhibition. CARM1 inhibition was shown to limit H3R17 methylation, resulting in decreased H3K9 acetylation and HDAC9 dissociation [92]. Ellagic acid and other plant-derived substances are strongly bound with the multiple targets of the SARS-CoV-2 receptors, inhibiting viral entry, attachment, binding, replication, transcription, maturation, packaging, and spread [93].

2.12. Epigallocatechin Gallate

Epigallocatechin gallate (EGCG) is the most abundant catechin in tea leaves, comprising 50–80% of the total catechins [94]. EGCG was recognized as the primary contributor to the numerous health benefits associated with green tea [94], including a reduction in the symptoms of infectious diseases [95]. EGCG binds to various targets and exerts its influence on the activity of diverse enzymes and signal transduction pathways [96]. Studies with animal models and various cancer cell lines have shown that EGCG and other catechins modulate the activity of DNMTs [97]. Fang et al. suggested that EGCG inhibited DNMT activity, resulting in the reactivation of methylation-silenced genes [98]. In fact, EGCG can reduce DNA methylation through the direct inhibition of the activity of DNMT 1, DNMT 3a, and DNMT 3b, by directly binding to the active site within the enzyme [97]. EGCG also regulates histone modifications by inhibiting the activity of HDACs [99] and consequently inducing changes in gene expression patterns. The inhibition of HDAC activity by EGCG results in a decrease in HDAC enzyme activity and consequently leads to increased levels of acetylation on histone proteins both globally and at specific regions. In human colon cancer cell lines, EGCG inhibited HDAC1, HDAC2, and HDAC3 expression [100]. In addition, EGCG inhibited histone acetyltransferase (HAT) activity [101]. EGCG has been demonstrated to prompt the increased acetylation of lysine 14 and 9 (on histone H3) and lysine 12, 5, and 16 (H3-Lys and H4-Lys) levels [102].  EGCG has also been implicated as a potential modulator of miRNAs by regulating the expression levels of epigenetic modifiers or viral proteins. EGCG has been reported to decrease the levels of let-7e-5p, miR-103a-3p, miR-151a-5p, miR-195-5p, miR-222-3p, miR-23a-3p, miR-23b-3p, miR-26a-5p, miR-27a-3p, miR-29b-3p, miR- 3195, miR-3651, miR-4281, miR-4459, miR-4516, miR-762, and miR-125b-5p [103]. Another study showed that EGCG enhances the expression of miR-3663-3p, miR-1181, miR-3613-3p, miR1281, and miR-1539, while decreasing miR-221-5p, miR-374b, miR-4306, miR-500a-5p, and miR590-5p in human dermal papilla cells [104] and miR-140-3p and miR-221 in melanoma and hepatoma cell lines, respectively [105][106]. The anti-viral properties of EGCG have been demonstrated for a wide range of virus families, including Retroviridae, Orthomyxoviridae, and Flaviviridae.  EGCG also exerts anti-viral activity by modulating miRNA expression, such as upregulating miR-548m expression. Reports found miR-548m binding sites in the 3′UTR of CD81 mRNA′. This suggests that miR-548m may lower the expression of CD81, which would make HCV less likely to infect cells. These results suggest that EGCG may act as an anti-HCV drug by increasing the expression of miR-548m while decreasing the expression of the CD81 receptor required for HCV infection [107].  The liver-specific miR-122 [108] is the most abundant miRNA in the liver, accounting for 60–70% of the total miRNA in hepatocytes. Many investigations have found that miR-122 is required for HCV replication in infected cells [109][110][111]. EGCG (and also resveratrol) modulates the expression levels of miR-122 and thus might exert an anti-HCV effect via this mechanism. IAV infection caused a significant decrease in micro-RNA let-7 expression in host cells that normally regulate the expression of type I interferon required for the host cells’ anti-viral activity. The overexpression of let-7 increased the expression of the interferon and effectively inhibited the IAV infection. EGCG upregulates the expression of let-7 and thereby has the potential to exhibit anti-influenza activity [112] (Figure 1).
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Figure 1. Anti-viral activity of EGCG against IAV, HPV, and HCV viruses. HCV replication is dependent on host CD81 and host miR-122. EGCG upregulated miR-548m expression, which in turn regulates CD81 expression and downregulates miR-122 (also mediated by other bioactive substances such as resveratrol) to exert anti-HCV activity. IAV infection caused a significant decrease in microRNA let-7 expression which is required for regulating expression of type I interferon. EGCG and other bioactive substances, such as quercetin, upregulate let-7 to increase interferon expression and effectively inhibit IAV infection.

2.13. Galangin

Galangin is a naturally occurring flavonoid found in honey that is also an active ingredient in galangal, a spice used in traditional Chinese medicine [113]. This natural compound appears to effectively inhibit HDAC activity. In SH-SY5Y human neuroblastoma cells, treatment with galangin increased endogenous HDAC1-mediated deacetylation independently of DNA methylation status and subsequently decreased histone H3 acetylation in BACE1 promoter regions [114]. Galangin upregulates miR-455-5p to modulate the regulatory subunit 12A of protein phosphatase 1 (PPP1R12A). This effect suppresses the activation of the MAPK and the phosphoinositide 3-kinases/protein kinase B (PI3K/AKT) pathways, controlling cancer cell survival and metastasis [115]. Galangin showed significant antiviral activity against HSV-1 and Coxsackie B1 (CoxB1) [116].

2.14. Garcinol

Garcinol is a polyisoprenylated benzophenone isolated from the peel of the Garcinia indica Choisy fruit [117]. Garcinol has anti-cancer, anti-inflammatory, and antioxidant properties [118]. In tumor cells, it primarily inhibits the NF-κB and Janus kinase (JAK)/STAT3 transcription factors [117]. Garcinol has been shown to decrease the HAT activity of p300 and pCAF in vitro and in vivo [119]. As a result, garcinol was discovered to be a potent inducer of apoptosis and to affect global gene expression in HeLa cells [119]. The chemical structure of garcinol shows some similarities with curcumin (β-diketone, phenol). Garcinol has shown significant anticancer activity by targeting NF-κB, 5-lipoxygenase (5- LOX), and STAT proteins [120][121].

2.15. Genistein

Genistein is a naturally occurring isoflavone isolated from the plant Genista tinctoria [122] and is well known for its potential chemotherapeutic action against a variety of cancer cells. Studies on HAT and HDAC activity revealed that genistein reduces HDAC while increasing HAT activity [122]. In prostate cancer cell lines, a chromatin immunoprecipitation analysis with multiple antibodies revealed the enrichment of acetylated histones H3, H4, and H3 di- and tri-methylated lysine 4 after incubation with genistein [123]. Furthermore, genistein inhibited the phosphorylation of serine 10 and the methylation of lysine 9 in the promoter regions of several genes, including wingless-related integration site (Wnt5a), as well as induced the secretion of frizzled-related protein 5 (Sfrp5), and frizzled-related protein 2 (Sfrp2) [124].

2.16. Ginkgolic Acid

Ginkgolic acid (GIA) is a phenolic acid found in Ginkgo biloba L. with neuroprotective, antimicrobial, and antitumor properties [125]. Ginkgo biloba has been used in traditional Chinese medicine since at least the 11th century BC to treat various ailments, such as dementia, asthma, bronchitis, and kidney and bladder diseases. Ginkgolic acid is a potent multitarget inhibitor of key enzymes in the biosynthesis of proinflammatory substances [125]. Ginkgolic acid impairs SUMOylation by blocking the formation of an E1-SUMO thioester complex by binding directly to E1 [126]. SUMOylation is a process by which small ubiquitin-related modifier proteins (SUMO) covalently bind to specific lysine residues in target proteins, thereby regulating various aspects of protein function, including transcription, subcellular localization, DNA repair, and the cell cycle [127]. JMJD2A, a member of the Jumonji domain 2 (JMJD2) family, is the histone demethylase responsible for the accumulation of SUMO-2/3. JMJD2A is SUMOylated at lysine 471 by Kaposi’s sarcoma-associated herpesvirus (KSHV) K-bZIP, a viral SUMO-2/3-specific E3 ligase, in a SUMO-interacting motif (SIM)-dependent manner. SUMOylation is required for the stabilization of chromatin association and gene transactivation by JMJD2A [128]. Recently, ginkgolic acid was reported to inhibit HSV-1 by disrupting the virus’ structure, blocking fusion, and inhibiting viral protein synthesis [129].

2.17. Glycyrrhizic Acid

Glycyrrhizic acid (GA) is a triterpene isolated from the roots and rhizomes of licorice (Glycyrrhiza glabra L.)) [130]. GA is the principal bioactive ingredient of licorice with anti-viral [131], anti-inflammatory, and hepatoprotective effects [132]. The licorice plant is native to Europe and Asia and has been used for centuries in traditional medicine. Ancient documentations from China, India, and Greece stated that it was traditionally used to alleviate the symptoms of viral respiratory tract infections and hepatitis [130]. Licorice is known for its ability to inhibit the viral replication of various viruses including HBV, HCV, IAV H1N1, and HIV, as reviewed by Zhong et al. [133]. Licorice extract containing glycyrrhiza inhibited the replication of Newcastle disease virus (NDV) and was non-toxic in an embryonic egg assay [134]. Glycyrrhizin exhibited antiviral activity by affecting cellular signaling pathways and increasing the expression of nitrous oxide synthase (NOS) [135]. Presumably by controlling the expression of the NF-κB and PI3K signaling pathways, glycyrrhizin’s anti-inflammatory impact may be obtained [136]. Glabridin licorice (Glycyrrhiza glabra) contains significant amounts of the isoflavan glabridin, which demonstrated anti-inflammatory and neuro- and cardioprotective activities in addition to distinct anti-cancer properties (growth inhibition as well as anti-angiogenic and anti-metastatic effects [137][138][139]. Glabridin suppressed cancer stem-cell-like features in hepatocellular carcinoma cells by the upregulation of miR-148a that targets SMAD2 (mothers against decapentaplegic homolog 2) associated with the inhibition of TGF (transforming growth factor)-β/SMAD2 signaling [140][141].

2.18. Grifolin

Grifolin is an adenosine derivative isolated from the fresh fruiting bodies of the fungus Albatrellus confluens (Alb. & Schwein.) Kotl. & Pouz. [142]. Grifolin was shown to suppress tumor cell lines’ proliferation. Grifolin inhibited Bcl-2 expression while increasing Bax expression [142]. Grifolin reduced ETS Like-1 protein (Elk1) transcription as well as its binding to the DNMT1 promoter region. The mRNA levels of pTEN and tissue inhibitor of metalloproteinases 2 (Timp2) Timp2 are likewise increased by griforolin. Grifolin’s anti-tumor effects may be exerted by ERK1/2-Elk1-DNMT1 signaling’s epigenetic activation of metastasis-inhibitory genes [143].

2.19. Oleacein

Oleacein, a secoiridoid [144], is the most prominent phenolic compound in Olea europaea L. (olive). This substance exhibited anti-cancer activity against multiple myeloma cell lines (NCI-H929, RPMI-8226, U266, MM1s, and JJN3) and was found to be an effective epigenetic modulator. Oleacein was reported to downregulate several class I/II HDACs both at the mRNA and protein level; conversely, no effect on global DNA methylation was associated with this compound [145][146]. Oleacein inhibited the proliferation of numerous melanoma cell lines [147]. It has been shown that oleacein can stop HIV-1 infection, replication, and the production of the viral core antigen p24 [148].

2.20. Organosulfur Chemicals

Organosulfur chemicals (OSC) are a group of compounds found in garlic (Allium sativum L.). More than thirty sulfur-containing compounds have been identified so far [149]. Garlic extracts were found to have broad-spectrum anti-viral activity [150]. Conversely, the mechanism by which these extracts or their purified constituents exert anti-viral activity may differ depending on the virus strains and viral lifecycle, which includes viral entry, fusion, replication, assembly, and virus–host-specific interactions [151]. Garlic has been used as an ethnomedicinal herb to cure infectious diseases for ages [152]. It has been utilized to treat a variety of illnesses in African traditional medicine, including sexually transmitted diseases, Mycobacterium tuberculosis (TB), respiratory tract infections, and wounds [153][154]. Garlic was shown to have effects against viral infections in humans, animals, and plants. In addition to garlic extracts or powders, purified bioactive components from garlic also exhibited anti-viral activity. As an example, alliin (S-allyl-L-cysteine sulfoxide), which is the most abundant sulfur compound found in fresh and dry garlic [155], is rapidly converted into allicin (diallyl thiosulfinate) by alliinase enzymes when fresh garlic is chopped, minced, crushed, or chewed [155][156]. Allicin is the primary component responsible for its anti-viral activity [157][158], immunomodulatory characteristics [159], anti-inflammatory [160] and antioxidant [161] activities, and other pharmacological properties. Allicin is very unstable and breaks down into other OSCs, such as andajoen, vinyl dithiins, diallyl disulfide (also known as garlicin or DADS), diallyl trisulfide (also known as allitridin or DATS), and diallyl disulfide (also known as DAS). In vivo, allicin can interact with cellular thiols such as glutathione and L-cysteine to form S-allyl mercapto glutathione (SAMG) and S-allyl mercaptocysteine (SAMC) [162][163]. These compounds may be responsible for structural changes in pathogen proteins [156]. Preclinical in vitro and in vivo studies have shown that allicin-derived OSCs such as ajoene, allitridine, garlicin, and DAS have antiviral [164][165][166][167][168], immunostrengthening [169][170][171], and other therapeutic activities [162][172][173].

2.21. Orobol 7-O-d-Glucoside

Orobol 7-O-d-glucoside (O7G) isolated from banaba Lagerstroemia speciosa L. (Lythraceae) [174] was tested for its anti-viral efficacy against eight different strains of HRV, a cause of common viral respiratory tract disease [174]. O7G displayed anti-viral activity against HRV A and B, as well as species resistance to pleconaril, a potent capsid inhibitor of HRVs [175].

2.22. Orsaponin

Orsaponin (OSW-1) is a natural substance derived from the bulbs of the plant Ornithogalum saundersiae which has anti-proliferative and anti-cancer properties [176]. Enteroviruses (EV) use oxysterol-binding protein (OSBP) as a host lipid transport protein [177]. Several studies have shown that OSW-1 binds to one of the two identified OSBP ligand-binding sites and exerts prophylactic antiviral activity against all enteroviruses tested, including EV71, coxsackievirus A21 (CVA21), and HRV-B [178][179].

2.23. Plitidepsin

Plitidepsin is a cyclic depsipeptide isolated from the Mediterranean marine tunicate Aplidium albicans [180]. Plitidepsin is made and sold as alpidine, a drug that has been approved for a limited number of uses to treat multiple myeloma. Its target is eukaryotic translation elongation factor 1A (eEF1A) [181]. This cellular component is necessary for enzymes to move aminoacyl-tRNAs to the ribosome. It has also been found to be an important host factor in the replication of many viruses, such as RSV and gastroenteritis coronavirus [182].

2.24. Pterostilbene

Pterostilbene (3,5-dimethoxy-4-hydroxystilbene) is a bioactive chemical found in grapes and several berries, mainly blueberries [183]. Pterostilbene alters gene expression in breast cancer cells, which are mediated by epigenetic mechanisms such as HDAC modifications [184]. It inhibits SIRT1 and regulates cell proliferation, apoptosis, stress response, metabolism, cellular senescence, and cancer [184][185].

2.25. Quercetin

Quercetin is a flavonoid found in many medicinal plants and food products [186]. This compound has a variety of biological properties, including anticancer activity, through several modes of action. Quercetin, alone or in combination with other drugs, promotes epigenetic modifications. It enhances histone H3 acetylation via FasL overexpression, the activation of HAT, and the inhibition of HDAC activities [187]. Furthermore, quercetin reduced HMT activities, particularly HMT-H3K9 activity [46].

2.26. Raoulic Acid

Raoulic acid isolated from Raoulia australis [12] has shown possible anti-viral activity against coxsackievirus B3 (CVB3) and coxsackievirus B4 (CVB4), as well as HRV types A and B [12].

2.27. Resveratrol

Resveratrol (3,5,4′-trihydroxystilbene) is a bioactive molecule isolated by Saiko et al. [188] from the roots of white hellebore (Veratrum grandiflorum Loes.). More than 50 plant species contain this bioactive substance, including grapes, apples, blueberries, plums, and peanuts. It has been intensively researched for its health benefits against a variety of diseases, including cancer [189]. Resveratrol treatment increased p21 expression in Caski cells via the inhibition of HDAC [190]. HDAC activity is decreased by resveratrol in a dose-dependent manner [191]. Pterostilbene is a phytoalexin dimethyl ether molecule that is a dimethoxylated derivative of resveratrol [192].

2.28. Silibinin

Silibinin is a flavonolignan derived from milk thistle [193] and has powerful anticancer effects, targeting multiple checkpoints, including epigenetic processes such as HDAC activity. Silibinin was shown to inhibit the expression of HDAC2 and HDAC3 proteins, as well as HDAC1, HDAC6, SET domain proteins (SETD1A, D4, D6), and lysine-specific demethylases (KDM 5B, 5C, and 4A) are some of these [124]. Silibinin also inhibited the expression of HDAC1-2 in DU145 and PC3 human prostate cancer cell lines [194].

2.29. Silvestrol

Silvestrol, isolated from Aglaia plants [195], has been shown to target eukaryotic initiation factor-4A (eIF4A), an RNA helicase whose activity is required to unravel RNA secondary structures in the 5’-untranslated region (5′-UTRs) and facilitate translation initiation [196]. Silvestrol showed activity against EBOV, ZIKV, CHIKV, and coronaviruses [197][198][199].

2.30. Sulforaphane

Sulforaphane (1-isothiocyanato-4(methylsulfinyl)butane) (SFN) is an isothiocyanate present mostly in cruciferous vegetables including broccoli, cabbage, brussel sprouts, and radishes [200]. In breast cancer cells, SFN significantly reduced HDAC activity [201] and increased the expression of acetylated histones H3 and H4 [201]. Moreover, SFN enhanced the expression of the anti-oncogene proteins dual-specificity phosphatase 4 (DUSP4) and cyclin-dependent kinases (CDKs), which are associated with the downregulation of the HDAC5 and HDAC11 genes in the hepatocarcinoma HepG2 cell line [202]. A further benefit of SFN is that it increases let-7 expression, which may have anti-IAV effects [112].

2.31. Tanshinone IIA

Tanshinone IIA is a natural bioactive compound found in Salvia miltiorrhiza Bunge’s rhizome [203]. Wang et al. investigated tanshinone IIA’s role in epigenetic modifications, demonstrating its effect on HDAC modification [204]. This bioactive molecule decreased the enzymatic activity of HDACs. Tanshinone IIA significantly reduced the protein levels of HDAC1, HDAC3, and HDAC8 by lowering mRNA expression [204]. Tanshinone IIA was reported to be an inhibitor of MAPK p38 [205]. MAPK p38 is explored by many viruses for their efficient replications [206]. Natural products that inhibit MAPK p38 activity might be a good candidate to exhibit broad-spectrum anti-viral activity [205], including DENV [60], coronavirus [61], Venezuelan equine encephalitis virus (VEEV) [62], EV71 [63], severe fever with thrombocytopenia syndrome virus (SFTSV), HSV-1, and SARS-CoV-2 [205][206].

2.32. Ursolic Acid

Ursolic acid (3-beta-3-hydroxy-urs-12-ene-28-oic-acid) is a triterpenic acid found in ginseng (Panax Ginseng C. A. Meyer), rosemary (Rosmarinus officinalis L.), apple peel, pear, cranberry, and plum (Prunus domestica L.) [207]. It has been extensively studied for its chemopreventive and chemotherapeutic effects on a variety of malignancies. Ursolic acid significantly reduces the expression of various epigenetic regulatory factors, including HDAC1, HDAC2, HDAC3, and HDAC8 (Class I), as well as HDAC6 and HDAC7 (Class II) [208].

2.33. Withaferin A

Withaferin A (WFA) is a steroidal lactone derived from the plant Withania somnifera (L.) Dunal [209], known for its anticancer properties and ability to target several cancer hallmarks such as cell proliferation, migration, invasion, and angiogenesis, as well as the epigenetic process [209]. WFA displayed chemopreventive benefits by reversing epigenetic alterations via the downregulation of HDAC1 protein levels [209].

3. Conclusions

Not all bioactive substances that alter epigenetic modifications were reported to have anti-viral activity. On the other hand, other bioactive substances exhibited anti-viral activity without any evidence of epigenetic effects. This suggests that epigenetic pathways might contribute to the anti-viral effect of these bioactive compounds, but are not the exclusive mechanisms explaining their action. This missing information will need to be evaluated experimentally.

It has shown that a variety of bioactive compounds can modulate epigenetic modifications such as DNA methylation, histone modifications, and miRNA expression. Bioactive substances such as EGCG, apigenin, curcumin, quercetin, berberine, resveratrol, genistein, silibinin, and sulforaphane were particularly interesting for their complex effect on different epigenetic pathways. Some bioactive substances, such as ellagic acid, tanshinone IIA, selenium, cordyceptin, grifolin, andrographolide, ursolic acid, corosolic acid, and betulinic acid, can affect just one epigenetic mark, while others, such as EGCG, showed activities on all epigenetic features.

It should be noted that not all bioactive chemicals that influence the activity of epigenetic mediators have been evaluated for anti-viral activity. Others showed anti-viral efficacy but without a definite mechanism of action. Some bioactive substances showed anti-viral activity against a limited number of viruses, whilst others were efficient in inhibiting a wide range of viruses. Some bioactive substances have a broad-spectrum anti-viral activity, inhibiting both RNA and DNA viruses.

Several bioactive agents exhibited a broad spectrum of antiviral activities against both RNA and DNA viruses. For example, baicalin, sulforaphane, apigenin, ginkgolic acid, andrographolide, EGCG, resveratrol, berberine, quercetin, curcumin, and glycyrrhizic acid showed inhibitory effects on 5, 5, 9, 11, 12, 13, 13, 14, 17, and 18 distinct viruses, respectively.

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