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Flavonoids as Nutraceuticals. Rajesh K. Kesharwani, Deepika Saini, Raj K. Keservani, and
Anil Kumar Sharma (Eds.)
© 2024 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)
CHAPTER 4
THERAPEUTIC ANTIVIRAL POTENTIAL
OF FLAVONOIDS
RUCHI RANI, MANDAR BHUTKAR, and SHAILLY TOMAR
Department of Bioscience and Bioengineering, Indian Institute of
Technology, Roorkee, Uttarakhand, India
ABSTRACT
Flavonoids are well-known naturally occurring biomolecules founds to be
effective antivirals. These biomolecules can act directly and indirectly at
various steps of viral infection. Flavonoids from plants serve as an untapped
reservoir of therapeutically active constituents that needs to be explored
as potential antiviral candidates against RNA and DNA viruses. Further,
structure-based studies can play a crucial role in identifying antiviral activity
showing flavonoids. Despite many efforts, very few flavonoids are in clinical
trials for antiviral treatment against various virus infections. Here, flavonoids
as evidence-based natural sources of antivirals against a number of classes of
viruses have been discussed.
4.1 INTRODUCTION
Infectious diseases have been known to humans since ancient times. The
emergence, dissemination, and persistence of these diseases remain a
pressing worldwide health concern. These diseases are caused by various
microbes such as viruses, bacteria, protozoa, fungi, and others. Humans
and viruses are always at odds, and viruses are constantly upgrading their
attack and defense strategies against humans, which is associated with high
mortality and morbidity. The current global context implies that viral disease
increases rapidly due to unprecedented climate change and globalization.
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58 Flavonoids as Nutraceuticals
In recent years, there has been significant progress in understanding the
genetic basis and molecular mechanism of many infectious diseases. The
prevalence of viral infections, which impact several million individuals each
year, has heightened interest in the antiviral potential of naturally occurring
flavonoids. Synthetic antiviral molecules frequently have limited efficacy
and substantial side effects, while flavonoids being natural molecules have
no side effects. With growing worldwide awareness of nutrition and health,
the inclusion of naturally occurring flavonoids in the diet provides health
benefits against various viral diseases and helps in improving human health
(
Keservani & Sharma, 2014; Keservani et al., 2010a, b, 2020).
Flavonoids are naturally occurring secondary plant metabolites with
a polyphenolic structure in barks, roots, stems, and plant by-products
(Middleton, 1998). Long before avonoids were identied as the active
ingredients, these natural chemicals were known for their health benets.
Flavonoids have been placed in over 4,000 different types, many of which
are responsible for the appealing colors of owers, fruit, and leaves (De
Groot
& Rauen, 1998). Flavonoids are benzo-γ-pyrone derivatives struc-
tures that are ubiquitously present in plants. They have two aromatic rings
(A and B) connected by a heterocyclic pyran-4 ring (C) (
Figure 4.1). The
C2–C3 double bond and the C ring's 4-oxo functional group are essential
components in avonoids' biological activity (Takano-Ishikawa et al., 2006).
Flavonoids are classied into subgroups based on the degree of unsatura
-
tion and oxidation of the C-ring and the B-ring linkage to the carbon of the
C-ring. Flavonoids in which the B ring is attached to the C3 and C4 position
of the C ring are known as isoavones and neoavonoids, respectively. In
contrast, the B ring attached to the C2 position of the C ring is further clas-
sied into many subgroups based on the structural features of the C ring.
The following subgroups are avonols, avanonols, avones, avanones,
catechins, chalcones, and anthocyanins.
FIGURE 4.1 The basic structure of flavonoids.
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Therapeutic Antiviral Potential of Flavonoids 59
Flavonoids’ chemical properties are determined by their degree of
hydroxylation, structural class, degree of polymerization, and various substi
-
tutions and conjugations (Heim et al., 2002). Even though avonoids possess
numerous health benets and are widely available in human diets, researchers
face obstacles to using these natural compounds as therapeutic choices in the
clinical context. The absorption and bioavailability of avonoids in humans
are the main hindrances inuenced by factors such as glycosylation, pKa,
esterication, molecular weight, lipophilicity, and interactions with enteric
bacteria, and other metabolic conjugations along the alimentary tract (
Cook
& Samman, 1996; Hollman & Katan, 1998; Jaganath et al., 2006; Makino et
al., 2009; Hollman et al., 1999; Scalbert et al., 2002; Yao et al., 2004). As a
result, efforts to improve the bioavailability of avonoids when consumed by
humans are critical for turning these natural molecules into viable antiviral
therapeutics. To improve their bioavailability, researchers have tried several
approaches to increase the solubility of substances or to move the absorption
site in the gut. Structural changes in avonoids that resulted in a shift in
the site of the large-to-small intestine for absorption increased the intake of
avonoids in individuals. In addition to solubility, the approach that boosts
the bioavailability of the avonoids is by increasing the dissolving rate and
permeability of avonoids, limiting their degradation and metabolism in the
gastrointestinal tract, and directly delivering the avonoids to their physi
-
ological targets (Puranik et al., 2019; Scalbert et al., 2002).
Recent curiosity in these substances has been sparked by the potential
health benets arising from the antiviral (Dejani et al., 2021; Ninfali et al.,
2020; Kaul et al., 1985; Zandi et al., 2011), antimicrobial (Gutiérrez-Venegas
et al., 2019;
Cushnie & Lamb, 2005), anti-parasitic (Liu et al., 1992; Mead &
McNair, 2006; Stermitz et al., 2002), antioxidant (Forester & Lambert, 2011;
Heim et al., 2002; Pietta, 2000), anti-inammatory (Maleki et al., 2019),
anti-carcinogenic (Adhami & Mukhtar, 2006; Forester & Lambert, 2011;
Seelinger et al., 2008; Imran et al., 2019; Qadir, 2017; Yang & Wang, 2011),
anti-mutagenic (Miyazawa et al., 1999, 2000, 2001; Miyazawa & Hisama,
2003) as well as other benecial activities of these polyphenolic compounds.
4.2 FLAVONOIDS AS ANTIVIRAL
Flavonoids (Keservani & Sharma, 2014) are effective against DNA as well
as RNA viruses. The virus is an obligatory parasite that is incapable of
propagating on its own. However, once a virus infects a susceptible cell, it
can direct its machinery to produce more viruses. Viruses can infect various
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60 Flavonoids as Nutraceuticals
cells, including animals, bacteria, plants, humans, yeast, protozoa, and
archaea. The diversity of nucleic acids found in viruses is astonishing. The
size and complexity of viruses’ nucleic acid vary greatly from few as 2,000
bases to more than 2 × 10
6
bases, leading to coding capacities extending from
2 to over 2,000 proteins. If we compare it with the human genome, it is 3.2 ×
10
9
bases long, or almost 2 × 10
5
times longer. Among these different classes
of viruses, (+) RNA viruses are the largest group of eukaryotic viruses that
can infect insect, mammalian, and plant hosts.
In this chapter, the antiviral potential of avonoids has been discussed.
Albert Szent-Gyorgyii presented the rst evidence of avonoids’ biological
activity in 1938, demonstrating that orange peel avonoids decrease capillary
bleeding and fragility associated with scurvy (Samuelsson, 1999). After that,
a broad spectrum of biological activities has been dened for avonoids. The
research for antiviral compounds extracted from plants began in the 1950s
when extracts of 288 plants were shown to have antiviral action against the
inuenza A virus in embryonated eggs (Chantrill et al., 1952). Flavones’
antiviral activity has been examined and documented since the 1990s when
synergistic antiviral potential of apigenin and 5-ethyl-2′-deoxyuridine on
the multiplication of herpes simplex virus type 1 (HSV-1) and pseudorabies
virus (
Mucsi, 1984) were studied in vitro. While in 1992, apigenin exhibited
a synergistic effect with acyclovir in cell culture on HSV-1 and HSV-2
(Beladi, 1992). Although, apigenin structure was initially recognized in
1900 (Li et al., 1997) and synthesized in 1939 (Hutchins & Wheeler, 1939).
Aside from these viruses, apigenin has been shown to have antiviral activity
against the African swine fever virus (ASFV), DNA virus (Hakobyan et al.,
2016), and picornaviruses, RNA virus (
Lv et al., 2014; Qian et al., 2015). In
addition, the antivirals have been intensively explored for other avones like
baicalein (Johari et al., 2012; Zandi et al., 2012), hydroxy avone (Wang et
al., 2013, 2014; Kawser et al., 2014), luteolin (Fan et al., 2016; Peng et al.,
2017, 2018; Shadrack et al., 2021; Shawan et al., 2021), and wogonin (Choi
et al., 2015; Guo et al., 2007; Seong et al., 2018; Chu et al., 2020).
Recently, avonols are also reported to be effective against poliovirus 1,
HSV-1, and 2 (Amoros et al., 1992; Lyu et al., 2005) and respiratory syncy-
tial virus (RSV) (Barnard et al., 1993). While one of the potential avonols,
quercetin showing activity against different viruses such as inuenza A
virus (Ha et al., 2014; Wu et al., 2016), HSV-1, HSV-2 (Hung et al., 2015),
Japanese Encephalitis Virus (JEV) (Johari et al., 2012), ZIKA virus (ZIKV)
(Wong et al., 2017), Ebola virus (Qiu et al., 2016), hepatitis B virus (HBV)
(Cheng et al., 2015), hepatitis C virus (HCV) (Gonzalez et al., 2009), murine
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61 Therapeutic Antiviral Potential of Flavonoids
coronavirus (CoV) and dengue virus (DENV) infection (Chiow et al., 2016),
porcine epidemic diarrhea virus (Choi et al., 2009), anti-Mayaro virus
(MAYV) (dos Santos et al., 2014), etc. Other avonols and their derivatives,
such as glycoside rutin, sulfated rutin, kaempferol, setin, etc., also act as
antivirals against different viruses.
4.2.1 MOLECULAR INHIBITION TARGETS
Flavonoids with antiviral activity should have the following properties:
no toxicity in healthy cells, high efficacy for numerous viral diseases, oral
consumption capability, and inexpensive cost. Different flavonoids have
been discovered to inhibit the virus by various mechanisms. Flavonoids
can function as therapeutic inhibitors or indirect immune system inhibitors
based on antiviral modes of action. The following categories can be found
in flavonoids that can suppress viral activity (i) They can suppress viruses
inhibition from attaching to or entering the host cells (
Table 4.1); (ii) inhibi-
tors of viral replication in the early stages (Table 4.2); (iii) blockers for tran-
scription and translation (Table 4.3); (iv) blocking late phases of maturation,
such as assembly, packaging, and release (Table 4.4); and (v) flavonoids that
can prevent viral infections by interfering with host components necessary
for infection or by regulating the immune system to decrease viral titer. To
multiply and thrive, viruses rely on the metabolism of their hosts and their
surroundings. So, they misuse and take over the host's cellular machinery
and spread throughout the body (Table 4.5).
TABLE 4.1 Viruses Targeted by Different Flavonoids Attachment or Entry Stage
Flavonoids Virus In Vitro/In Vivo References
Quercetin JEV Vero cells Johari et al. (2012)
Rhinovirus BEAS-2B and C57BL/6 mice Ganesan et al. (2012)
Influenza A 293T cells, Madin Darby Canine Wu et al. (2016)
virus Kidney (MDCK) cells, and human lung
epithelial A549 cells.
HCV Human embryonic kidney (HEK) 293T. Rojas et al. (2016)
HSV-1 and Vero cells Lyu et al. (2005)
HSV-2
HSV-1 Raw 264.7 cells and Vero cells Lee et al. (2017)
Luteolin Epstein-Barr rAkata cells with TW01 cells Wu et al. (2017)
virus (EBV)
DENV AG129 mice Peng et al. (2017)
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62 Flavonoids as Nutraceuticals
TABLE 4.2 Viruses Targeted by Different Flavonoids at the Early Viral Replication Stage
Flavonoids Virus In Vitro/In Vivo References
Quercetin DENV-2 Vero cells Zandi et al. (2011b)
HCV Human embryonic kidney Rojas et al. (2016)
(HEK) 293T.
HSV-1 Raw 264.7 cells and Vero Lee et al. (2017)
cells.
HBV HepG2.2.15 cells and Bai et al. (2016)
BALB/c mice.
JEV Vero cells Johari et al. (2012)
Mayaro viruses Vero cells dos Santos et al. (2014)
Luteolin Enterovirus 71 and 293T cells, RD cells Xu et al. (2014)
Coxsackievirus a16 (human embryonal
rhabdomyosarcoma), and
Vero cells.
JEV A549 cells Fan et al. (2016)
Baicalein JEV Vero cells Johari et al. (2012)
Influenza A/FM1/1/47 BALB/c mice Xu et al. (2010)
(H1N1) virus
Influenza A/FM1/1/47 MDCK cells Chen et al. (2011)
(H1N1) virus.
Apigenin EV71 Vero cells Lv et al. (2014)
Vaccinia virus HeLa cells, MDCK cells, Chang et al. (2009)
HuH7 cells, and Con1
cells.
TABLE 4.3 Viruses Targeted by Different Flavonoids at Transcription and Translation Stage
Flavonoids Virus In Vitro/In Vivo References
Quercetin HCV
In silico studies
Fatima et al. (2014)
SARS-CoV
In silico study
Ryu et al. (2010)
Apigenin Enterovirus (EV71) Vero cells Lv et al. (2014)
Foot-and-mouth disease (FMD) BHK-21 cells Qian et al. (2015)
EBV rAkata cells Wu et al. (2017)
SARS-CoV
In silico study
Ryu et al. (2010)
Luteolin SARS-CoV
In silico study
Ryu et al. (2010)
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63 Therapeutic Antiviral Potential of Flavonoids
TABLE 4.4 Viruses Targeted by Different Flavonoids at the Assembly, Packaging, and
Release Stage
Flavonoids Virus In Vitro/In Vivo References
Quercetin HCV Humanembryonic Rojas et al. (2016)
kidney (HEK) 293T
Canine distemper virus Vero cells González-Búrquez et al.
(2018)
HCV Human embryonic Rojas et al. (2016)
kidney (HEK) 293T.
Luteolin DENV 1–4 AG129 mice Peng et al. (2017)
Baicalin Strain A/Thailand/K
Insilco studies
Veerasamy & Rajak. (2021)
(H3N2)
Biochanin A H5N1 influenza A virus A549 cells and Vero Sithisarn et al. (2013)
and baicalein cells
TABLE 4.5 Viruses Targeted by Different Flavonoids by Interfering with the Host
Components
Flavonoids Virus In Vitro/In Vivo References
Quercetin HSV-1 Raw 264.7 cells and Vero cells Lee et al. (2017)
Luteolin JEV BHK-21 and Raw264.7 cells
Li et al. (2014)
Biochanin H5N1 influenza A A549 cells and Vero cells Sithisarn et al. (2013)
A and virus
baicalein
Apigenin EV71 Vero cells Lv et al. (2014)
Hepatitis C virus Huh7 and 293T cells Shibata et al. (2014)
4.2.2 FLAVONOIDS AGAINST VIRUS CLASSES
Emerging and re-emerging viral pathogens have become increasingly
important throughout the world in recent decades, as they have substantial
impacts on human health and economic wealth. Infectious diseases can jump
from animal to human or human to human either directly through contact
or indirectly through contaminated inanimate objects, intermediate hosts,
bites of insect vectors, etc. (Parrish et al., 2008). According to the Baltimore
classification, viruses can be placed in one of the seven following groups
mentioned in Table 4.6. Viruses can have circular and linear double-stranded
deoxyribonucleic acid (dsDNA), circular or linear single-stranded (ss)
DNAs, ds ribonucleic acid (RNAs), positive and negative-strand RNAs ('+'
strand and '–' strand RNAs, respectively). The primary distinction between
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64 Flavonoids as Nutraceuticals
'+' strand RNAs and '-' strand RNA viruses is that '+' strand RNAs viruses
can be directly translated into proteins, whereas '-' strand RNA viruses refer
to the encoding of the viral proteins by the complementary strand. Some
RNA viruses are ambisense, which means they contain both the RNAs, ‘+’
and ‘-’ strands. While some individual virus particles contain multiple RNA
fragments, which form the viral genome and are all required for successful
virus replication. Although some viral particles have RNA, when the virus
infects a new host cell, this RNA is transcribed into DNA.
TABLE 4.6 Baltimore Classification of Viruses with Their Examples
Classes Viruses Mode of mRNA Synthesis Examples
Class I dsDNA dsDNA is used to replicate the
viral genome that is further used
for mRNA synthesis.
Adenoviruses,
Papillomaviruses, polyoma
-
viruses, Herpesviruses, Pox
viruses
Class II ssDNA viruses ssDNA genome replicates
to dsDNA, then mRNA is
synthesized.
Parvoviruses
Class III dsRNA viruses dsRNA genome transcribed to
mRNA.
Reoviruses
Class IV (+) ssRNA
viruses
+ssRNA virus genome functions
as mRNA
Togaviruses, Coronaviruses,
Picornaviruses
Class V (–) ssRNA
viruses
–ssRNA is complementary to the
viral mRNA.
Orthomyxoviruses,
Rhabdoviruses
Class VI ssRNA-reverse Genome first converted to dsDNA Retroviruses
transcriptase
(RT) viruses
viruses through reverse transcrip-
tion. Further, dsDNA is integrated
into the host cell.
Class VII dsDNA-RT
viruses
Replicate through an RNA
intermediate.
Hepadnaviruses,
Caulimovirus
4.2.2.1 FLAVONOIDS AGAINST DSDNA VIRUSES
Herpesviridae family consists of human dsDNA viruses such as HSV,
varicella-zoster virus (VZV), HCMV, EBV. HSV infections include gingi-
vostomatitis, herpes genitalis, herpetic keratitis, and dermal whitlows, while
VZV infection causes chickenpox in children and further reactivation of the
latent virus in adults causes herpes zoster called shingles. EBV and HCMV
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65 Therapeutic Antiviral Potential of Flavonoids
cause infectious mononucleosis; however, EBV is associated with Burkitt’s
lymphoma and other malignancies (Whitley, 1996) (virus pathogen database
and analysis resource (ViPR) – Herpesviridae). Quercetin and Isoquercitrin
strongly suppressed the expression of VZV and HCMV immediate-early (IE)
genes (Kim et al., 2020). Dihydromyricetin from Ampelopsis grossedentata
has shown the Anti-HSV-1 effect via the toll-like receptor 9 (TLR9) depen-
dent anti-inflammatory pathway (Zhou et al., 2020). Various flavonoids such
as epicatechin, epigallocatechin (flavonols), genistein (isoflavone), narin
-
genin (flavanone), and quercetin (flavonol) showed a high level of inhibitory
activity for HSV-1 and HSV-2 (Lyu et al., 2005). Moreover, (–)-Epigallocate
-
chin-3-gallate (EGCG) inhibits EBV spontaneous lytic infection via ERK1/2
and PI3-K/Akt signaling (
Liu et al., 2013). Furthermore, quercetin-induced
apoptosis prevents EBV infection (
Lee et al., 2015) (Table 4.7).
TABLE 4.7 dsDNA Viruses and Flavonoids
Family Viruses Flavonoids Mechanism of Action References
Herpesviridae
VZV and
HCMV
HSV-1
HSV-1
and
HSV-2
EBV
EBV
Quercetin and
Isoquercitrin
Dihydromyricetin
Epicatechin,
epigallocatechin,
genistein, naringenin,
and quercetin.
(–)-Epigallocatechin-
3-gallate
Quercetin
Expression of immediate- Kim et al.
early (IE) genes (2020)
TLR9-dependent anti- Zhou et al.
inflammatory pathway. (2020)
Not mentioned Lyu et al.
(2005)
ERK1/2 and PI3-K/Akt Liu et al.
signaling. (2013)
Apoptosis pathway Lee et al.
(2015)
4.2.2.2 FLAVONOIDS AGAINST SSDNA VIRUSES
Parvovirus B19 (B19V) is an ssDNA virus from the Parvoviridae family. It
is a human pathogenic virus responsible for many clinical manifestations.
Usually, infections are mild, self-limiting, and controlled by developing a
specific immune response. Still, in many cases, clinical situations can be
more complex and require therapy (Manaresi & Gallinella, 2019). In the
in vitro study, various flavonoid structures inhibited endonuclease activity
of the non-structural protein 1 (nsP1) of Parvovirus B19 (Xu et al., 2019)
(Table 4.8).
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