Viral Disease and Use of Polyphenolic Compounds

C H A P T E R

25 Viral Disease and Use of Polyphenolic Compounds Dong Joo Seo, Changsun Choi Department of Food and Nutrition, School of Food Science and Technology, College of Biotechnology and Natural Resources, Chung-Ang University, Anseong-si, Republic of Korea

Abbreviations 50 -UTR ATF-2 cccDNA CCL-2 CREB CVA16 CXCL-1 CXCL-2 DENV DNA EGCG eIF EV71 FCV GCG HA HBV HCV HFMD HIV hnRNPs HSV IFN-α IFN-γ IFN-λ IL-1β IL-6 IL-8 iNOS IP-10 IRES JEV JNK LXR M MDCK MNV NA NF-kB NoV

50 -untranslated region activator of Fe transcription 2 covalently closed circular DNA chemokine (C-C motif) ligand 2 cyclic AMP response element-binding protein coxsackievirus A16 chemokine (C-X-C motif) ligand 1 chemokine (C-X-C motif) ligand 2 dengue virus deoxyribonucleic acid epigallocatechin gallate eukaryotic translation initiation factor enterovirus 71 feline calicivirus gallocatechin gallate hemagglutinin hepatitis B virus hepatitis C virus hand, foot, and mouth disease human immunodeficiency virus heterogenous nuclear ribonucleoproteins herpes simplex virus interferon alpha interferon gamma interferon lambda interleukin 1β interleukin 6 interleukin 8 inducible nitric oxide synthetase interferon γ-induced protein 10 internal ribosomal entry site Japanese encephalitis virus c-Jun N-terminal kinase liver X receptor matrix protein Madin-Darby canine kidney murine norovirus neuraminidase nuclear factor kappa B human norovirus

Polyphenols: Prevention and Treatment of Human Disease https://doi.org/10.1016/B978-0-12-813008-7.00025-4

NP NS NTCP OAS ORF PI3K RdRp RNA RNP ROS RSV SAR SaV TK TLR TNF-α TV VZV VP WNV ZIKV ZAP

nucleocapsid protein nonstructural protein sodium taurocholate cotransporting polypeptide 20 -50 oligo (A) synthetase open reading frame phosphoinositide 3-kinase RNA-dependent RNA-polymerase ribonucleic acid ribonucleoprotein reactive oxygen species respiratory syncytial virus structure activity relationship sapovirus thymidine kinase Toll-like receptor tumor necrosis factor alpha tulane virus varicella-zoster virus viral protein West Nile virus Zika virus zinc finger CCCH type antiviral protein 1

1 POLYPHENOLIC COMPOUNDS Polyphenolic compounds are secondary metabolites that are present in fruits, vegetables, nuts, cereals, and beverages [1,2]. They have strong antioxidant activity and contribute to odor, flavor, bitterness, and color in foods. Based on the number of phenol rings and chemical structure, they are mainly classified into phenolic acids, flavonoids, stilbenes, and lignans (Fig. 25.1). Phenolic acids are divided into two main classes, hydroxybenzoic acids and hydroxycinnamic acids [1,2]. Hydroxycinnamic acids are more common phenolic acids than hydroxybenzoic acids. Hydroxycinnamic acids, including caffeic acid, ferulic acid, coumarinic acid, sinapic acid, and chlorogenic acid, are found in various fruits,

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25. VIRAL DISEASE AND USE OF POLYPHENOLIC COMPOUNDS

Hydroxy-cinnamic acid

Hydroxy-benzoic acid

Stilbene

Flavonoid

Lignan

FIG. 25.1 Chemical structures of polyphenolic compounds.

coffee, rice, oats, wheat, corn, and potato. Hydroxybenzoic acids, including gallic acid, protocatechuic acid, and p-hydroxybenzoic acid, are present in red fruits, black radish, and onions. Flavonoids are classified into flavonols, flavanols, flavanones, flavones, isoflavones, and anthocyanins [2,3]. Flavonols including quercetin and kaempferol are most common flavonoids. The main sources are yellow onions, curly kale, leeks, broccoli, and blueberries. Flavanols are present as catechins (monomer form) and proanthocyanidins (polymer form). Catechins are commonly derived from beans, fruits (apricot, cherry, grape, peach, blackberry, and apple), tea (green tea and black tea), and red wine. As condensed tannins, proanthocyanidins contribute to the astringent taste in fruits (grapes, peaches, berries, pears, apples, etc.), tea, beer, and wine. Flavanones consist of hesperetin, naringenin, and eriodictyol, which are abundant in citrus fruits (grapefruit, oranges, and lemons). Flavones such as apigenin and luteolin are found in parsley and celery. Isoflavones are similar with estrogen structure and their main classes are daidzein, genistein, and glycitein. Leguminous plants (soybean) are main sources of the isoflavones. Anthocyanins contribute to red, purple, pink, and blue color in fruits, vegetables, and flowers. They are abundant in aubergine, blackberry, black currant, blueberry, black grape, cherry, and rhubarb. Stilbenes are present in leaves, barks, roots, and rhizomes in nonedible plants (Dipterocarpaceae, Cyperaceae, Gnetaceae, Pinaceae, etc.) [2,4]. Although stilbenes are present with low content in human diets, resveratrol,

which is representative of stilbenes, is found in grapes, grape juice, and wine. Lignans are phytoestrogens rich in oleaginous seeds, such as linseed. They are also contained in cereal, fruit (pears and prunes), and vegetables (carrot, garlic, and asparagus). Polyphenolic compounds have been known to have antioxidation, anticancer, antidiabetic, anticardiovascular disease, and antineurodegenerative activity that is beneficial and therapeutic effects in human health [5]. Antiviral polyphenolic compounds were reported in several studies against RNA viruses (norovirus surrogates, rotavirus, enteroviruses, influenza A and B viruses, respiratory syncytial virus, human immunodeficiency virus-1, hepatitis C virus, Japanese encephalitis virus, dengue virus, West Nile virus, and Zika virus) and DNA viruses (hepatitis B virus, herpes simplex virus, and varicella-zoster virus) (Table 25.1). However, mechanisms underlying antiviral effect were not investigated in depth.

2 THE REPLICATION CYCLE OF VIRUS AND THE TARGET OF ANTIVIRAL ACTIVITY The replication cycle of viruses generally consists of attachment, entry, uncoating, replication, assembly/maturation, and release (Fig. 25.2). Viral attachment is the first step for a virion to interact with the specific receptors on the host cells using viral capsid proteins or phospholipid envelope. Their specificity determines the host

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TABLE 25.1

303

Antiviral Polyphenolic Compounds and Their Target Viruses Described in Previous Publications

Target viruses

Viral genomes

Polyphenolic compounds

Targets

References

RNA VIRUSES (NONENVELOPED VIRUSES) Feline calicivirus

Single-stranded RNA

Flavonoid (myricetin and L-epicatechin)

Viral capsid protein integrity?

[6]

Feline calicivirus

Single-stranded RNA

Flavonoid (theaflavin)

Viral entry?

[13]

Murine norovirus

Single-stranded RNA

Flavonoid (theaflavin)

Viral entry?

[13]

Porcine sapovirus

Single-stranded RNA

Flavonoid (theaflavin)

Viral entry?

[13]

Murine norovirus

Single-stranded RNA

Flavonoid (quercetin, fisetin, and daidzein)

Rotavirus

11 Segmented doublehelix RNA

Flavonoid (genistein)

Viral capsid protein (VP6) synthesis

[18]

Flavonoid (EGCG and α-glucosyl hesperidin)

Viral capsid protein (VP6) integrity

[20]

Flavonoid (licocoumarone, glyasperin C, glyasperin D, glycyrin, licoflavonol, and 2’methoxyisoliquiritigenin)

Viral absorption and replication

[21]

Stilbenoid (trans-arachidin-1 and transarachidin-3)

Viral replication

[22]

Flavonoid (apigenin)

Viral replication

[24]

Flavonoid (apigenin)

–

[25]

Flavonoid (luteolin)

Viral replication

[27]

Flavonoid (EGCG)

Viral replication

[28]

Enterovirus 71

Single-stranded RNA

[14]

Rhinovirus

Single-stranded RNA

Flavonoid (quercetin)

Viral replication and protein synthesis

[7]

Coxsackie virus B3

Single-stranded RNA

Flavonoid (7-O-galloyltricetifavan and 7,4’-di-Ogalloyltricetifavan)

–

[36]

Poliovirus 1

Single-stranded RNA

Flavonoid (EGCG)

Virucidal effect

[72]

RNA VIRUSES (ENVELOPED VIRUSES) Influenza A (H5N1) virus

Single-stranded RNA

Flavonoid (biochanin A and baicalein)

Viral replication (biochanin A and baicalein) Viral release (baicalein)

[8]

Influenza A (H9N2) virus

Single-stranded RNA

Flavonoid (EGCG)

Viral replication

[31]

Influenza A (H1N1) and B viruses

Single-stranded RNA

Flavonoid (theaflavin and kaempferol)

-

[32]

Influenza A (H1N1) and B viruses

Single-stranded RNA

Flavonoid (isoquercetin)

Viral proteins (hemagglutinin and matrix protein 1) synthesis

[33]

Influenza A (H3N2) virus

Single-stranded RNA

Ellagitannin (punicalagin)

Viral entry

[34]

Influenza A (H1N1 and H3N2) and B viruses

Single-stranded RNA

Phenolic Acid (gallic acid)

Viral integrity

[35]

Influenza A (H1N1) virus

Single-stranded RNA

Flavonoid (7-O-galloyltricetifavan and 7,4’-di-Ogalloyltricetifavan)

–

[36]

Respiratory syncytial virus

Single-stranded RNA

Flavonoid (7-O-galloyltricetifavan and 7,4’-di-Ogalloyltricetifavan)

–

[36]

Stilbenoid (resveratrol)

–

[38] Continued

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25. VIRAL DISEASE AND USE OF POLYPHENOLIC COMPOUNDS

Antiviral Polyphenolic Compounds and Their Target Viruses Described in Previous Publications—cont’d

Target viruses

Viral genomes

Polyphenolic compounds

Targets

Human immunodeficiency virus-1 (HIV-1)

Single-stranded RNA

Flavonoid (baicalin)

Viral entry

[40]

Flavonoid (EGCG)

Viral entry

[41]

Flavonoid (theaflavin)

Viral protein (glycoprotein 41) synthesis

[42]

Flavonoid (EGCG)

Viral entry

[44]

Flavonoid (EGCG and delphinidin)

Viral entry

[45]

Flavonoid (quercetin)

Viral replication

[46]

Hepatitis C virus

Single-stranded RNA

References

Japanese encephalitis virus

Single-stranded RNA

Flavonoid (baicalein)

Viral entry and replication, and virucidal effect?

[48]

Dengue virus type-2

Single-stranded RNA

Flavonoid (quercetin, daidzein, and naringin)

Viral integrity and entry

[49]

Dengue virus type-2

Single-stranded RNA

Flavonoid (EGCG and delphinidin)

Virucidal effect

[50]

West Nile virus

Single-stranded RNA

Virucidal effect

Zika virus

Single-stranded RNA

Virucidal effect

Zika virus

Single-stranded RNA

Flavonoid (EGCG)

Viral entry

[51]

Circular doublestranded DNA

Flavonoid (EGCG)

Viral entry

[54]

Flavonoid (EGCG)

Viral replication

[55]

Flavonoid (EGCG)

Viral replication

[56]

Flavonoid (baicalin)

Viral replication

[57]

Phenolic Acid (chlorogenic acid, quinic acid, and caffeic acid)

Viral replication

[58]

DNA VIRUSES Hepatitis B virus

Herpes simplex virus type 1 and 2

Double-stranded DNA

Flavonoid (EGCG)

Viral entry

[61]

Herpes simplex virus type 1

Double-stranded DNA

Flavonoid (palmitoyl-EGCG)

Viral entry

[62]

Procyanidin B2-3,3’-di-O-gallate

Viral integrity

[63]

Herpes simplex virus type 1

Double-stranded DNA

Stilbenoid (resveratrol)

Viral replication

[66]

Herpes simplex virus type 1 and 2

Double-stranded DNA

Oligomeric stilbenoids

Viral protein (infected cell polypeptide 0) synthesis

[67]

Herpes simplex virus-2

Double-stranded DNA

Phenolic acid (protocatechuic acid)

–

[69]

Herpes simplex virus type 1

Double-stranded DNA

Flavonoid (7-O-galloyltricetifavan and 7,4’-di-Ogalloyltricetifavan)

–

[36]

Human herpesvirus type 3 (Varicella-zoster virus)

Double-stranded DNA

Stilbenoid (resveratrol)

Viral protein (transcriptional regulatory protein) synthesis

[71]

range (tropism) and target tissues of a virus. The viral envelope of attached virions fuses with the cellular membrane. Some viruses can enter the host cell through receptor-mediated endocytosis. Then, viral enzymes or

host enzymes remove and degrade the viral capsid to release the viral RNA or DNA. After uncoating, transcription or translation of the viral genome is initiated. In this stage, each virus has unique replication process

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3 ANTIVIRAL POLYPHENOL COMPOUNDS AGAINST RNA VIRUSES

FIG. 25.2

Inhibitory steps of antiviral polyphenols during virus life cycle. Step #1: virus entry, Step #2: viral replication, Step #3: viral protein packaging, Step #4: assembly, Step #5: release.

Step #1 Entry

Step #3

Step #2 Translation Viral genome replication

Protein packaging

Assembly

Step #4

Intracellular cell signaling

Release

Step #5 Cytokine genes expression Nucleus

depending on the viral genome (DNA versus RNA) and its nucleic acid polarity. After de novo synthesis of viral genome and proteins in replication, a newly replicated viral genome with viral proteins undergoes packaging process. In maturation, newly packaged virions are ready to be released from the host cell. Viruses use two strategies to release their virions out of host cells: lysis or budding. Cytolytic virus causes the lysis of an infected host cell to release new virions. As the enveloped viruses, such as influenza A virus, obtain viral envelope from host cell membrane, cytopathic viruses are typically released by budding process without killing the infected cell. Antiviral activity of polyphenols may differ depending on the time point of treatment and virus. Pretreatment, cotreatment, and posttreatment of polyphenols were used for the inhibition of virus [6–8]. When compounds are treated on cells or animal models prior to virus infection, the pretreatment effect is a preventive effect associated with viral attachment or entry (Fig. 25.2). As compounds are simultaneously treated with the virus, cotreatment of polyphenols is associated with virucidal effect to destroy the integrity of the viral capsid or genome. When compounds are treated on virus-infected cells or animals, posttreatment of polyphenols may indicate a therapeutic effect associated with viral replication, assembly, and release (Fig. 25.3). Till now, many studies have reported on the antiviral or inhibitory effect of polyphenols on various RNA/ DNA viruses. Although antiviral targets of polyphenols are discussed, the exact mechanisms of antiviral polyphenols have not been understood clearly. Therefore, this chapter deals with antiviral polyphenolic compounds and their mechanisms against RNA and DNA viruses.

3 ANTIVIRAL POLYPHENOL COMPOUNDS AGAINST RNA VIRUSES 3.1 Human Norovirus and Its Surrogates Human norovirus (NoV) is the leading cause of viral gastroenteritis worldwide. As NoV is highly resistant to drying, extreme pH and temperature, they can survive in water, foods, and environment. They can be transmitted by foodborne, waterborne, airborne, fomite route, and person-to-person contact [9]. To date, many attempts using many different cell lines and three-dimensional cell culture have failed to cultivate NoV, although the use of B cell line or human intestinal enteroid were recently reported to amplify NoV successfully. The antiviral drugs or polyphenols against NoV have not been tested directly [10]. Therefore, feline calicivirus (FCV), murine norovirus (MNV), porcine sapovirus (porcine SaV), tulane virus (TV), and MS2 male-specific coliphage have been developed as NoV surrogates because they have similar physical and chemical characteristics to NoV in the family Caliciviridae. Although there are disputes about the suitability of NoV surrogates, FCV and MNV have been used to investigate the effect of sanitizers, food components, and polyphenols in many studies [11,12]. Interestingly, the inhibitory activity of myricetin, L-epicatechin, theaflavin, quercetin, fisetin, and daidzein against several NoV surrogates were observed in an in vitro model [6,13,14]. While the cotreatment of myricetin and L-epicatechin inhibited FCV only, the cotreatment of theaflavin reduced FCV, MNV, and porcine SaV. Their inhibitory mechanism was suggested to be interference with viral entry in the cell surface or destruction of viral integrity [6,13]. In other studies, the pretreatment of

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25. VIRAL DISEASE AND USE OF POLYPHENOLIC COMPOUNDS

quercetin, fisetin, and daidzein on RAW 264.7 cells reduced MNV titers significantly more than cotreatment or posttreatment [14]. As the cotreatment and posttreatment of them did not affect MNV titer, immune responses are suspected as an antiviral mechanism rather than direct interference on MNV replication. The expression of inflammatory cytokines, interferons, and interferonstimulated genes (ISGs) was up-regulated in RAW 264.7 murine macrophage cells pretreated with quercetin, fisetin, and daidzein. Especially, the induction of interferon-α (IFN-α), IFN-λ, and tumor necrosis factor-α (TNF-α) on RAW 264.7 cells contributed to reduce the MNV titer. Instead of 20 -50 oligo (A) synthetase (OAS), the expression of Mx and zinc finger CCCH type antiviral protein 1 (ZAP) play a role to reduce MNV replication [14].

3.2 Rotavirus (RV) Rotavirus (RV) causes approximately 611,000 deaths per year for children under 5 years. Its clinical symptoms are severe: viral gastroenteritis with diarrhea, fever, abdominal pain, and vomiting [15]. RV, belonging to the family Reoviridae, is a nonenveloped 11-segmented double-stranded RNA virus. The segments of the RV genome consist of VP1, VP2, VP3, VP4, VP6, VP7, NSP1, NSP2, NSP3, NSP4, and NSP5/NSP6. RV has seven serologic groups (Group A to G). Each serogroup has multiple serotypes. The pathogenesis of RV is known in animals and humans because RV group A, B, and C are found in both human and animals. With the destruction of enterocytes, villous ischemia, enterotoxins, the stimulation of enteric nervous system, or disruption of enterocyte absorptive functions results in malabsorption diarrhea of RV infection; primary treatment is to replace the loss of fluids and electrolytes by excessive diarrhea and vomiting [16]. Savi et al. compared 60 different flavones and flavonols to inhibit RV titer in vitro. The structure-activity relationships (SAR) analysis of them demonstrated that the presence of two or more methoxyl and ethoxyl radicals of the flavonols was associated with the reduction of RV titer on MA-104 cells. But, flavonols containing only one methoxyl or ethoxyl radical did not reduce RV titer [17]. Many flavonoids (EGCG, genistein, genistin, licocoumarone, glyasperin, glycyrin, licoflavonol, glyasperin D, and α-glucosyl hesperidin as synthetic forms of glucose and hesperidin) and stilbenoids (trans-arachidin-1 and trans-arachidin-3) also showed the antiviral effect against RV [18–22]. Genistein is the most studied soy isoflavone in vitro and in vivo. The cotreatment of genistein inhibited the synthesis of VP6 RNA and protein. It decreased RV titer in human colon carcinoma Caco-2 cells [18]. In addition, the inhibitory mechanism of genistein was linked with

the activator of Fe transcription 2 (ATF-2), cyclic AMP response element-binding protein (CREB), and NF-κB transcription factors. The activation of cAMP/PKA/ CREB cell-signaling pathway up-regulates the expression of aquaporin (AQP)-4 on Caco-2 cells. As the AQP-4 transports water across the cell membrane, genistein may reduce diarrheal symptoms of RV infection by abnormal expression of AQP. The consumption of soybased infant formula (SBIF) helped to reduce the symptoms of viral infection in vitro and in vivo. When the individual isoflavones and the mixture in soy-based infant formula were compared, genistin (genistein aglycone) and isoflavone mixture inhibit RV titer [19]. Similarly, epigallocatechin gallate (EGCG) and α-glucosyl hesperitin reduced integrity of capsid protein (VP6) when they co-treated with simian RV strain SA-11 [20]. Polyphenols derived from the roots of Glycyrrhiza uralensis inhibited bovine and porcine RV in TF-104 fetal rhesus monkey kidney cells [21]. The cotreatment of glyasperin C, glyasperin D, glycyrin, licocoumarone, and licoflavonol with RV interfered with the viral absorption through hemagglutination inhibition. The posttreatment of glyasperin C, glyasperin D, licocoumarone, licoflavonol, 20 -methoxyisoliquiritigenin, transarachidin-1, and trans-arachidin-3 reduced synthesis of NSP3 or NSP4 nonstructural viral RNA and protein on RV-infected cells [21,22].

3.3 Enteroviruses Enteroviruses are positive-sense single-stranded RNA viruses in the family Picornaviridae. Poliovirus, coxackievirus, enterovirus, and rhinovirus were the Enterovirus species in the traditional classification. The new classification of the genus Enterovirus consists of 13 species: Enterovirus A, Enterovirus B, Enterovirus C, Enterovirus D, Enterovirus E, Enterovirus F, Enterovirus G, Enterovirus H, Enterovirus I, Enterovirus J, Rhinovirus A, Rhinovirus B and Rhinovirus C [23]. Enteroviruses cause a variety of symptoms including mild respiratory illness, hand, foot and mouth disease, encephalitis, acute hemorrhagic conjunctivitis, aseptic meningitis, myocarditis, neonatal sepsis-like disease, and paralysis [16]. Many studies have reported the inhibitory activities and mechanisms of polyphenolic compounds against various enteroviruses. In the genus Enterovirus, enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) cause hand, foot, and mouth disease (HFMD) in infants and young children. Although clinical symptoms of HFMD are generally self-limiting, EV71 infections result in severe conditions including pulmonary edema and aseptic meningitis, and even death. Apigenin inhibits the viral replication of EV71 but not CVA16. It also inhibits virus-induced cell apoptosis, the production of reactive oxygen species (ROS), the induction of inflammatory cytokines, and the internal

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ribosomal entry site (IRES) activity of EV71 [24]. Moreover, the antiviral mechanism of apigenin against EV71 was associated with heterogenous nuclear ribonucleoproteins (hnRNPs) in host cells rather than inhibition of 2Apro or 3Cpro cleavage activities. A pretreatment with apigenin disrupted the association of EV71 RNA and hnRNP A1 or A2 rather without changing the expression and localization of hnRNPs on RD cells. As EV71 IRES in the 50 -untranslated region (50 -UTR) is essential to initiate the viral translation, the trans-acting interference with hnRNPs and IRES by apigenin reduced EV71 replication [24,25]. Also, the inhibition of cellular c-Jun N-terminal kinase (JNK) activation by apigenin regulated EV71 infection [24]. It is still unclear whether the antioxidant properties of apigenin contribute to the antiviral mechanism because other highly antioxidative flavonoids did not inhibit EV71 replication [25]. From two-step screening from 400 natural compounds, luteolin was reported to inhibit both EV71 and CVA16 infection [26]. The inhibitory mechanism of luteolin was similar to that of apigenin except for the modulation of the cellular JNK pathway [24]. Luteolin also suppressed the interaction of hnRNPs and EV71 IRES, EV71 replication, and the production of cytokines and ROS. In the other side, luteoloside inhibited 3Cpro of EV71 in vitro [27]. Pretreatment with EGCG and gallocatechin gallate (GCG) demonstrated the inhibition of EV71 replication. The inhibition of viral protease and the RNA-dependent RNA polymerase (RdRp) gene by EGCG and GCG reduced the EV71 titer in African green monkey kidney cells (Vero cells) [28]. EGCG increased the viability of EV71-infected cells and suppressed reactive oxygen species generated by EV71. In addition, EGCG reduced the viral titers in glucose-6-phosphate dehydrogenasedeficient cells in which EV71 is more infective by oxidative environment. It is made clear that EGCG has cytoprotective effects as an antioxidant [28]. Quercetin was observed to have pre- and posttreatment effects against rhinovirus (RV) in BEAS-2B human lung bronchial epithelial cells [7]. Quercetin pretreated in BEAS-2B cells inhibited endocytosis of RV. It diminished Akt phosphorylation by RV, which inhibited the expression of IL-8. In addition, quercetin reduced viral titers, positive and negative strand RNA, and capsid protein (VP2) level after viral infection in BEAS-2B cells. The expression of cytokines such as IFN-β, IFN-λ1, IFN-λ2/3, and IL-8 were decreased. Furthermore, quercetin blocked cleavage of the eukaryotic translation initiation factor 4GI (eIF4GI) and increased phosphorylation of eIF2α, which may decrease viral RNA translation. In vivo, quercetin reduced RV titers and down-regulated levels of cytokines and chemokines in mice lungs. It significantly decreased IFN-α, IFN-λ2, TNF-α, chemokine (C-X-C motif) ligand 1 (CXCL-1), CXCL-2, and chemokine (C-C motif) ligand 2 (CCL-2) in lungs.

307

3.4 Influenza Virus Influenza viruses are enveloped viruses that belong to the family Orthomyxoviridae. Their genome consists of eight fragmented single-stranded RNAs: RNA-dependent RNA polymerase (RdRp), hemagglutinin (HA), neuraminidase (NA), nucleocapsid protein (NP), matrix proteins (M1 and M2), and nonstructural proteins (NS1 and NS2). Influenza viruses are divided into three types, type A, type B, and type C, based on nucleoproteins and genomic structure. Each of these types is further classified into various serotypes based on surface glycoproteins, HA and NA. Influenza A and B are strongly associated with the most common seasonal flu epidemics [29]. Tamiflu is a well-known antiviral drug that targets NA, which plays a role in cleaving the glycosidic bond linkages of sialic acids and releasing mature virions. Besides, HA, RdRP, and NP have been considered as therapeutic targets [30]. To date, over 250 papers have reported the inhibitory activity and the mechanism of various polyphenolic compounds against various influenza virus strains in vitro and in vivo models: flavonoids (biochanin A, baicalein, EGCG, and isoquercetin), ellagitannin (punicalagin), and phenolic acid (gallic acid) [8,31–36] (Fig. 25.3). Baicalein, apigenin, and luteolin reduced the neuraminidase activity of seasonal influenza A virus and H5N1 influenza virus while biochanin A did not inhibit the neuraminidase activity associated with virion release [8]. For the prevention and treatment of the influenza virus, several antiviral drugs were approved by the United States Food and Drug Administration: M2 ion-channel inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir, zanamivir, and paramivir). Interestingly, the combination of antiinfluenza drug with a flavonoid (biochanin A, baicalein, and EGCG) showed an additive or synergistic effect to reduce the viral titer more than the antiinfluenza drug alone. The posttreatment of biochanin A and baicalein reduced the viral titer on H5N1 influenza A virusinfected cells in a concentration-dependent manner. However, the pretreatment and cotreatment of them did not change viral titer [8]. Both flavonoids caused the nuclear retention of viral ribonucleoprotein (RNP) by the suppression of caspase-3 activation in host cells. When H5N1 influenza triggered the AKT, ERK1/2, JNK, p38 kinase pathways and secreted the various inflammatory cytokines, antiviral mechanisms of biochanin A and baicalein were regulated by a different cell signaling pathway. Biochanin A decreased the influenzainduced phosphorylation of AKT, ERK1/2, and the accumulation of nuclear factor-kappa B (NF-ĸB). On the contrary, the treatment of baicalein did not interfere with AKT, ERK1/2, and p38 pathways. Both inhibited the IL-6 and IL-8 secretion, and biochanin A but not baicalein reduced IFN γ-induced protein 10 (IP-10) on H5N1-infected cells.

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Entry

FIG. 25.3 Inhibitory mechanism of anti-

Punicalagin Gallic acid

viral polyphenols against influenza virus.

Biochanin A Baicalein EGCG

NF-KB

Intracellular cell signaling

Isoquercetin Translation

mRNA

Replication

Nucleus

Assembly Release

Biochanin A Baicalein Punicalagin

The antiviral effect of tea polyphenols against influenza A and B viruses has been studied in BALB/c mice and mouse pulmonary microvascular endothelial cells [31]. The interaction of laminin receptor and EGCG inhibited the toll-like receptor 4 (TLR4) signaling and NF-kB activation. The treatment of EGCG reduced lung injury, inflammatory cytokines (IL-1β and TNF-α), and myeloperoxidase in mice [31]. In the structure-activity relationship (SAR) analysis, the dimeric molecules such as theaflavin and procyanidin B-2 reduced influenza A virus titer more than catechin and flavonol monomers [32]. The inhibition of influenza B virus by kaempferol was associated with the planar flavonol structure with only one C-40 phenolic hydroxyl group in the B ring. In a comparison of plant-derived polyphenols, isoquercetin showed a potent inhibition against influenza A (H1N1) and B viruses rather than EGCG and quercetin in BALB/c mice and Madin-Darby canine kidney (MDCK) cells [33]. It reduced HA and M1 in influenza-infected MDCK cells. It also decreased viral titer, interferon-gamma (IFN-γ), CCL-5, inducible nitric oxide synthase (iNOS), and pathological lesion in the lung of mice challenged with influenza virus. Several polyphenolic compounds from pomegranate (Punica granatum), black raspberry (Rubus coreanus) seed, and Pithecellobium clypearia were identified to reduce influenza virus titer in an in vitro model. Although their precise mechanisms were not investigated, punicalagin interfered with the early viral replication, including viral absorption in H3N2 influenza

A-infected MDCK cells [34]. Black raspberry seed extract and its gallic acid interfered with hemagglutination and disrupted the virus particles, which was confirmed by transmission electron microscopy [35]. When two flavans, 7-O-galloyltricetifavan and 7,40 di-O-galloyltricetifavan, isolated from leaves of Pithecellobium clypearia, were simultaneously infected with H1N1 influenza A virus, it reduced viral titer on the MDCK cells [36].

3.5 Respiratory Syncytial Virus (RSV) Respiratory syncytial virus (RSV) is an enveloped negative-sense single-stranded RNA virus in the family Paramyxoviridae. It causes severe lung infections in young infants and children. Currently, vaccines are not available for the prevention and treatment of RSV infection [37]. Like influenza virus, the cotreatment of RSV with 7-Ogalloyltricetifavan and 7,40 -di-O-galloyltricetifavan reduced viral titer on vero cells. However, their inhibitory mechanisms were not elucidated [36]. Resveratrol suppressed the persistent airway inflammation of RSV, hyperresponsiveness, and viral replication [38]. The inhibition of IFN-γ and nerve growth factor production by resveratrol contribute to the reduction of inflammatory cells and airway hyperresponsiveness in RSV infectedlung tissues.

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3.6 Human Immunodeficiency Virus (HIV)

3.8 Other Viruses

HIV belonging to the family Retroviridae is a singlestranded positive-sense enveloped RNA virus. HIV divides into HIV-1 and HIV-2. HIV-1 has more high infectivity and virulence than HIV-2 globally [39]. HIV can infect immune-related cells such as helper T cells (CD4+ T cells), macrophages, and dendritic cells. A disorder of the immune system by HIV is called immunodeficiency syndrome (AIDS), in which the immune system no longer defends against opportunistic infections or cancers [39]. Flavonoids such as baicalein, EGCG, and theaflavin interfered with entry of HIV-1 to host cells [40–42]. Baicalein inhibited the fusion of recombinant vaccinia virus expressing the HIV-1 envelope protein gene in CD4 and chemokine (CXCR4 and CCR5) receptors expressed in cells. However, as baicalin did not inhibit binding of CD4 and gp120 viral envelope protein, chemokine receptors might be targets in early infection stage [40]. EGCG reduced expression of CD4 on CD4+ T cells and leukemia cell lines (U937 and HL-60 cells). It also inhibited binding of gp120 to the surface of EGCG-treated CD4+ T cells [41]. Theaflavin did not interact with CXCR4 and CCR5. In addition, theaflavin also did not interfere with binding of gp120 and CD4. It inhibited six-helix bundle formation of gp41, known as viral envelop glycoprotein 41, that is, it mediates fusion of HIV to host cells [42].

Japanese encephalitis virus (JEV), West Nile virus (WNV), Zika virus (ZIKV), and Dengue virus (DENV) are positive-sense single-stranded RNA and mosquitoborne viruses in the family Flaviviridae [47]. Many flavonoids including baicalein, quercetin, daidzein, naringin, delphinidin, and EGCG have been utilized in an attempt to control the replication of these viruses [48–51]. Baicalein degraded JEV structure and interfered with viral absorption and replication in Vero cells [48]. Although quercetin had no antiviral action against JEV, quercetin and daidzein exhibited an inhibitory effect in Vero cells before or after viral infection against DENV-2 [49]. Naringin also reduced DENV-2 titer when it was added to viruses directly [49]. EGCG and delphinidin decreased WNV infectivity when they were simultaneously treated with virus and added after viral infection in Vero cells [50]. As their antiviral action was not associated with interfering with viral fusion by endosomal acidification, the virucidal effect was hypothesized to be a possible antiviral mechanism against WNV. EGCG and delphinidin also exerted a virucidal effect against ZIKV and DENV. EGCG was more effective than delphinidin against WNV, ZIKV, and DENV. In recent reports, ZIKV treated with EGCG was inhibited in Vero E6 cells. It might disrupt viral entry or degrade the virus [51].

3.7 Hepatitis C Virus (HCV) Hepatitis C virus (HCV) is an enveloped single positive-stranded RNA virus belonging to the family Flaviviridae. It causes chronic infection in liver and consequently causes steatosis, fibrosis, liver cirrhosis, and hepatocellular carcinoma [43]. EGCG affected HCV entry into Huh-7.5 cells by blocking viral attachment to cell receptors [44]. It had no influence on the expression of cell receptors, scavenger receptor class B type I, claudin-1, and occludin. In another study, EGCG and delphinidin (anthocyanidin) disrupted cell attachment of the virus by altering viral particle structure [45]. Quercetin inhibited replication of HCV in huh7 cells bearing full length of HCV genotype 1b [46]. It reduced reactive oxygen and nitrogen and lipid peroxidation associated with liver damage. NS5A and core proteins of HCV are located on lipid droplets into cytoplasm and activate pathways related with lipid metabolisms. Quercetin decreased hepatic lipid accumulation by HCV infection. As liver X receptor (LXP) activation by phosphoinositide 3-kinase (PI3K)/AKT signaling pathway mediated lipid synthesis, it was also observed that quercetin reduced LXP gene expression and phosphorylated AKT protein levels.

4 ANTIVIRAL POLYPHENOL COMPOUNDS AGAINST DNA VIRUSES 4.1 Hepatitis B Virus (HBV) Hepatitis B virus (HBV) is known to cause chronic viral infection. About 350 million people have chronic infection and nearly 2 billion people are estimated to be infected globally. HBV infects through blood and semen causing chronic hepatitis, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. HBV is an enveloped double stranded DNA virus in the family Hepadnaviridae. HBV are divided into 10 genotypes, A to J. Genotype A is predominant in Northern Europe, North America, and Africa. Genotypes B and C mainly occur in Asia. The viral genome is 3.2 kb and has four open reading frames (ORFs) in which seven proteins are translated. Covalently closed circular DNA (cccDNA) serves as the template for transcription of viral RNA in the nucleus. And pregenome RNA is reverse transcribed into viral DNA. Nucleotide or nucleoside analogues were developed to block reverse transcription, but they do not directly affect cccDNA. As cccDNA is necessary for persistent infection of HBV, its removal is important to chronic HBV disease [52,53].

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EGCG reduced viral cccDNA, viral RNA, inner nucleocapsid core protein, and HBsAg production of HBV genotype A in HuS-E/2 cells and Huh7 cells transfected with sodium taurocholate cotransporting polypeptide (NTCP) as HBV receptor [54]. It also inhibited other HBV genotype B, C, and D infections in HuS-E/2 cells. EGCG elevated translocation of NTCP from plasma membrane to cytoplasm and degraded NTCP protein in Huh7 cells. In addition, it suppressed the clathrinmediated endocytosis of transferrin in HuS-E/2 cells. The antiviral action of EGCG was shown to be reducing viral entry. However, EGCG did not decrease viral DNA, viral RNA, core protein, HBeAg, and HBsAg levels in the human hepatocellular carcinoma. HepG2.2.15 cells transfected with the genome of HBV, which showed that EGCG did not inhibit viral replication, assembly, or release [54]. It was however also shown that EGCG inhibited viral DNA, HBsAg, and HBeAg levels in another human hepatocellular carcinoma HepG2.117 and Hep3B2.1-7 cells containing the HBV genome [55,56]. Similarly, baicalin, the glucuronide of baicalein, decreased extracellular viral DNA, viral mRNA, HBsAg, and HBeAg levels in HepG2.2.15 cells. This reduced the expression of hepatocyte nuclear factor to act as transcription factor. Baicalin showed a synergistic antiviral effect with entecavir (guanine analogue), an antiviral drug. In an in vivo study, baicalin and entecavir decreased viral DNA in blood and liver tissue of duck infected with HBV [57]. Chlorogenic acid, quinic acid, and caffeic acid, as subclasses of phenolic acids, inhibited DNA replication and HBsAg production in HepG2.2.15 cells. Chlorogenic acid and caffeic acid reduced DNA levels in serum of duck infected with HBV [58].

4.2 Herpes Simplex Virus (HSV) Herpes simplex virus (HSV) is an enveloped doublestranded DNA virus belonging to the Herpesviridae family. HSV DNA genome is 152 kb and includes immediate-early (IE), early (E), and late (L) genes encoding diverse viral proteins. IE genes including infected cell polypeptide (ICP0), ICP4, ICP22, ICP27, and ICP47 were immediately transcribed in the entry step. The transcription of IE genes is activated by viral protein (VP16). ICP0, ICP4, IC22, and ICP27 regulate the expression of the next genes, E and L genes. E genes encode proteins associated with viral replication such as DNA polymerase, thymidine kinase (TK), and ICP8. L genes are mostly translated to viral structure proteins such as glycoprotein, gC [59,60]. HSV is divided into HSV type 1 and 2. HSV-1 causes herpes infections on the mouth including cold sores and HSV-2, transmitted through sexual contact, is the main cause of genital herpes. To date, nucleoside and nucleotide analogues such as acyclovir, cidofovir, and foscarnet were used as antiviral drug against HSV. These are converted to acyclovir-

triphosphate by viral TK and cellular kinase, which act as competitive inhibitors of viral DNA polymerase, and are incorporated into viral DNA. HSV replication is blocked by preventing further elongation of nucleotides. However, resistant HSV against the drug acyclovir was reported in several studies. Therefore, new targets and natural products are required to prevent HSV. Antiviral effects of flavonoids (EGCG, palmitoylEGCG, 7-O-galloyltricetifavan, 7,40 -di-O-galloyltricetifavan, and procyanidin B2-3,30 -di-O-gallate), stilbenoids (resveratrol and oligomeric stilbenoids), and phenolic acids (protocatechuic acid) were reported against HSV [61–69]. Among them, a polyphenol mixture of green tea catechins including EGCG, EGC, GCG, GC, ECG, and EC inhibited HSV-1 and HSV-2. Oral administration of green tea catechins relieved HSV-1-induced skin lesion in mice [69]. EGCG directly interfered with the viral absorption of HSV [61,62]. EGCG reduced clinically isolated HSV-1 and HSV-2 titers. It showed direct degradation of HSV-1 virion by down-regulating viral glycoproteins gB and gD levels. However, EGCG did not abolish viral replication [61]. Similarly, EGCG and palmitoyl-EGCG decreased HSV-1 titers when each compound was cotreated with HSV-1. Palmitoyl-EGCG was more effective than EGCG against HSV-1. And it interfered with viral absorption to Vero cells. Both compounds reduced viral tegument protein VP11/12, glycoprotein gD, and US6 genes encoding gD [62]. In another study, flavan-3-ols and procyanidins from Rumex acetosa L. showed HSV-1 reduction. Among them, procyanidin B2-3,30 -di-O-gallate showed the most potent antiviral action against HSV-1 by inducing aggregation of glycoprotein gD [63]. Theaflavin-containing black tea extract inhibited viral absorption and penetration in A549 cells. VP11/12 encoded by UL46 gene was decreased when recombinant HSV-1 containing sequence of green fluorescent protein fused to UL46 was cotreated with black tea extract. Additionally, black tea extract down-regulated the gene of envelope glycoprotein, gD [64]. Resveratrol reduced HSV-1 DNA levels and expression of IE, E, and L viral genes including ICP0, ICP4, ICP8, DNA polymerase, and gC in Vero cells. HSV-1 infection is known to associate with host nuclear transcription factor (NF-ĸB) activation and induce antiapoptosis [65]. Resveratrol suppressed activation of NF-ĸB but did not block the translocation of NF-ĸB from the cytoplasm to the nucleus. And apoptosis was not observed by resveratrol [66]. In contrast to resveratrol, oligomeric stilbenoids did not suppress NF-ĸB activation. They inhibited HSV-1 and HSV-2 by inducing reactive oxygen species (ROS) [67]. Other polyphenolic compounds, 7-O-galloyltricetifavan and 7,40 -di-O-galloyltricetifavan, isolated from leaves of Pithecellobium clypearia, and protocatechuic acid from Hibiscus sabdariffa L. reduced HSV-1 and HSV-2 titers in Vero cells, respectively [36,68].

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REFERENCES

4.3 Varicella-Zoster Virus (VZV) Varicella-zoster virus (VZV) is an enveloped doublestranded DNA virus belonging to the family Herpesviridae [70]. VZV is also called human herpesvirus type 3. VZV infects the lungs and enters into the nerves, including the cranial nerve ganglia and dorsal root ganglia. It most commonly infects children with chickenpox (varicella), including respiratory symptoms and fever. However, herpes zoster (shingles) is dormant in older children. Resveratrol inhibited viral replication when it was treated in MRC-5 cells infected with VZV. Additionally, it decreased mRNA and protein levels of IE62, transcriptional regulatory protein. However, resveratrol did not affect viral attachment in cells and virucidal effect on VZV [71].

5 CONCLUSION Although many polyphenolic compounds have been used to reduce viral titers of various RNA and DNA viruses, inhibitory mechanisms of them still need to be elucidated. Because each virus has different receptors, structural stability, and viral replication cycle, antiviral polyphenols need to target various host and viral molecules, to reduce viral titer or replication. Interestingly, recent studies addressed how the combination of polyphenols and antiviral drugs acts synergistically to inhibit viral replication and to prevent the emergence of drug-resistant viruses. Further studies should be carried out to correlate antiviral activity of polyphenols and viral replication steps.

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