Received: 21 June 2021 Accepted: 24 September 2021

DOI: 10.1002/bab.2265

REVIEW ARTICLE

Multifaceted antiviral therapeutic potential of dietary

flavonoids: Emerging trends and future perspectives
Varruchi Sharma1 Nirmala Sehrawat2 Ajay Sharma3 Mukesh Yadav2
Pawan Verma4 Anil K. Sharma2

1Department of Biotechnology, Sri Guru

Gobind Singh College, Chandigarh, India
2Department of Biotechnology,
Maharishi Markandeshwar, Ambala,
Haryana, India
3
Department of Chemistry, Career Point
University, Hamirpur, Himachal Pradesh,
India
4Institute of Plant Sciences, Agricultural
Research Organization (ARO), Rishon
LeZion, Israel
Correspondence
Anil K. Sharma, Department of Biotech-
nology, Maharishi Markandeshwar
(deemed to be University), Mullana-
Ambala-133207, Haryana, India.
Email: anibiotech18@gmail.com
Abstract
Phytochemicals are the natural biomolecules produced by plants via primary or
secondary metabolism, which have been known to have many potential health
benefits to human beings. Flavonoids or phytoestrogens constitute a major group
of such phytochemicals widely available in variety of vegetables, fruits, herbs,
tea, and so forth, implicated in a variety of bio-pharmacological and biochem-
ical activities against diseases including bacterial, viral, cancer, inflammatory,
and autoimmune disorders. More recently, these natural biomolecules have been
shown to have effective antiviral properties via therapeutically active ingredients
within them, acting at different stages of infection. Current review emphasizes
upon the role of these flavonoids in physiological functions, prevention and treat-
ment of viral diseases. More so the review focuses specifically upon the antiviral
effects exhibited by these natural biomolecules against RNA viruses including
coronaviruses. Furthermore, the article would certainly provide a lead to the sci-
entific community for the effective therapeutic antiviral use of flavonoids using
potential cost-effective tools for improvement of the pharmacokinetics, bioavail-
ability, and biodistribution of such compounds for the concrete action along with
the promotion of human health.

KEYWORDS
antivirals, flavonoids, therapeutics, viral disease

1 INTRODUCTION tions including antioxidant, antiviral, anti-inflammatory,

Flavonoids are the polyphenolic, naturally occurring com-
pounds, which belong to the class of plant secondary
metabolites responsible for performing a variety of func-
Abbreviations: COVID-19, Coronavirus disease 2019; HCoVs, Human
coronaviruses; HSV-1 & HSV-2, Herpes simplex virus type 1 and 2;
ASFV, African swine fever virus; RSV, Respiratory syncytial virus;
EGCG, Epigallocatechin gallate; Anti-CHIKV, Anti-chikungunya; ZIKV,
Zika virus; DENV-2, Daidzein in dengue virus type 2; 3CLpro, 3C-like
protease; NAR, Naringenin.
anticancer properties along with health-promoting ben-
eficial effects.1,2 Flavonoids are known to play a dis-
tinct biological role in plants, animals, and bacteria. In
plants, they are accountable for the formation of color
and aroma of flowers, along with their ability to attract
pollinators in fruits.3 Moreover, many modern drugs are
based on the active flavonoid compounds derived from
plants themselves.4 Flavonoids are actually composed of
a group of secondary metabolites found in vegetables,
fruits, spices, red wine, and in tea as well, which play

© 2021 International Union of Biochemistry and Molecular Biology, Inc.

Biotechnol Appl Biochem. 2021;1–18. wileyonlinelibrary.com/journal/bab 1

2 SHARMA et al.
FIGURE 1 Basic classification of flavonoids
a defensive role against plant pathogens and insects.5,6
Considering the broad-spectrum antiviral role of the
flavonoids, this review emphasizes upon the bioactive
potential of major flavonoids against viral diseases includ-
ing the prevailing pandemic of coronavirus disease 2019
(COVID-19).7
2 CLASSIFICATION AND DIFFERENT
SOURCES OF FLAVONOIDS
The family of flavonoids has been classified into various
groups/subgroups, which is based on structural appear-
ance and the attachment of groups to the particular struc-
ture of flavonoids (Figure 1). For example, the flavonoids
in which there is a linking of the B ring at position 3 of
the C ring are called isoflavones. Also, the linking of B ring
in position 2 can be further subdivided into various sub-
groups based on the structural features of the C ring. The
subgroups are (a) flavones, (b) flavonols, (c) flavanones,
(d) flavanonols, (e) flavanols, (f) anthocyanins, and (g)
chalcones8 (Table 1; Figure 1).
3 FLAVONOIDS IN HUMAN HEALTH
Flavonoids play an important role in day-to-day life. The
ingestion of flavonoids is significantly associated with
longevity,9 along with their potential association with
inflammation and weight loss.10 The antioxidant and anti-
inflammatory behavior of flavonoids shows their associ-
ation with the anticipation of cardiovascular disease, as
these have the capability of lowering the risk of atheroscle-
rosis through protecting from free radical damage,11 along
with neurodegenerative diseases like Alzheimer’s and
Parkinson’s disease.12 In some of the studies, positive ther-
apeutic outcomes have been seen for certain cancers (lung,
mouth, stomach, colon, skin, etc.).13–15
4 FLAVONOIDS AS ANTIVIRALS
Coronaviruses (CoVs) are composed of single-stranded
RNA harboring the capability to cause infection in birds,
animals, as well as humans. Ranging from common cold
to serious pneumonia and bronchiolitis, human coron-
aviruses (HCoVs) have been found to be associated with
diverse array of respiratory disorders.16,17 Also in the cur-
rent context, CoVs are being rated as the fastest growing or
evolving viruses.18
Flavonoids being natural biomolecules are being con-
sidered to be effective antivirals (Figure 2), and significant
therapeutic effects have been observed at different stages
of viral infection.19 Multiple mechanisms have been pro-
posed for the flavonoid’s action; for example, they may
inhibit the viral attachment and entry into the host cells
(Figure 2). Flavonoids could interact with the host immune
system and may act as indirect antiviral inhibitors. More-
over, there are evidences where they have been proven as
prophylactic and therapeutic inhibitors.20 As flavonoids
constitute the largest group of phenolic natural com-
pounds widely distributed in the plant kingdom, they play
diverse roles as strong antioxidants, anti-inflammatory,
and antiallergic as well.21 Catalytic activities of a num-
ber of enzymes such as hexokinase, phospholipase/protein
kinase C, α-glucosidase, α-amylase, and so forth have been
reported to be inhibited by the action of these flavonoid
compounds.22
4.1 Apigenin
It has been established in cell culture studies that apigenin
along with acyclovir synergistically had improved antiviral
effects on the herpes simplex virus type 1 and 2 (HSV-1 and
HSV-2).23 Significant bioactivity against diverse classes of
viruses, including HSV-1, poliovirus type 2 and hepati-
tis C virus (HCV), and African swine fever virus (ASFV),
was observed upon using apigenin extracted from aster-
aceae plants.24,25 Another function attributed to apigenin
is to obstruct viral protein synthesis by suppressing inter-
nal ribosome entry site (IRES) activity.26,27 Another study
proved the antiviral effect of apigenin on HCV by bring-
ing about reduction in the mature microRNA122 that reg-
ulates HCV replication positively.28 In another study, api-
genin was shown to display a strong antiviral activity as
it suppressed the viral protein synthesis, especially having
pronounced effects against RNA viruses.29
4.2 Baicalein
Baicalein is another series of flavonoids that has been
found to be implicated as a best probable molecule
TA B L E 1 Structural features and diverse sources of major flavonoid compounds possessing significant antiviral properties
SHARMA et al.

S. No Flavonoid Source/s Chemical structures from pubchem Structural features Reference

Flavones
107
1 Baicalein From roots of ∙ Ring B linked at position 2 of
Scutellariabaicalensis ring C
and ∙ C2 =C3 bond and 4-oxo group
Scutellarialateriflora, in ring C
Oroxylumindicum ∙ Vicinal-trihydroxylated ring A
(5-,6-, and 7-OH groups)

2 Apigenin
108
Parsley, celery, celeriac, ∙ Ring B linked at position 2 of
and chamomile tea ring C
∙ Mono-hydroxylated ring B
(4ʹ-OH group)
∙ C2 =C3 bond and 4-oxo group
on ring C
∙ Meta-dihydroxylated ring A
(5- and 7-OH groups)

3 Luteolin
109,110
Celery, thyme, green ∙ Ring B linked at position 2 of
peppers, and ring C
chamomile tea, ∙ Ortho-dihydroxylated ring B
capers, apples, and (3ʹ and 4ʹ-OH groups)
onions ∙ C2 =C3 bond and 4-oxo group
on ring C
∙ Meta-dihydroxylated ring A
(5- and 7-OH groups)

(Continues)
3
 4

TA B L E 1 (Continued)
S. No Flavonoid Source/s Chemical structures from pubchem Structural features Reference
111,112
4 Tangeritin Peel of citrus fruits, ∙ 5-Methoxyl groups
mandarins, ∙ Such high level of
grapefruits, and methoxylation increases its
oranges hydrophobic character

Flavonols
109,113,114
1 Quercetin Leafy vegetables, ∙ Ring B linked at position 2 of
broccoli, red onions, ring C
peppers, apples, ∙ Ortho-dihydroxylated ring B
grapes, black tea, (3ʹ and 4ʹ-OH groups)
green tea, red wine, ∙ C2 =C3 bond, 3-OH and 4-oxo
and some fruit juices group in ring C
∙ Meta-dihydroxylated ring A
(5- and 7-OH groups)

115,116
2 Kaempferol Apples, grapes, ∙ Ring B linked at position 2 of
tomatoes, green tea, ring C
potatoes, onions, ∙ Mono-hydroxylated ring B
broccoli, Brussels (4ʹ-OH group)
sprouts, squash, ∙ C2 =C3 bond with 3-OH and
cucumbers, lettuce, 4-oxo groups on ring C
green beans, peaches, ∙ Meta-dihydroxylated ring A
blackberries, (5- and 7-OH groups)
raspberries, and
spinach, etc.

(Continues)
SHARMA et al.
 SHARMA et al.

TA B L E 1 (Continued)
S. No Flavonoid Source/s Chemical structures from pubchem Structural features Reference
117,118
3 Rutin Buckwheat, asparagus, ∙ Ring B linked at position 2 of
unpeeled apples, figs, ring C
black tea, green tea, ∙ Ortho-dihydroxylated ring B
and elderflower tea (3ʹ and 4ʹ-OH groups)
∙ C2 =C3 bond with
3-O-rutinoside and 4-oxo
group on ring C
∙ Meta-dihydroxylated ring A
(5- and 7-OH groups)

119,120
4 Fisetin Major sources are ∙ Ring B linked at position 2 of
strawberries apples, ring C
and grapes, onions, ∙ Ortho-dihydroxylated ring B
juices, wines, etc. (3ʹ and 4ʹ-OH groups)
∙ C2 =C3 bond with 3-OH and
4-oxo group on ring C
∙ Mono-hydroxylated ring A
(7-OH group)

(Continues)
5
 6

TA B L E 1 (Continued)
S. No Flavonoid Source/s Chemical structures from pubchem Structural features Reference
Flavans
121
1 Catechin Fresh tea leaves, red ∙ Ring B linked at position 2 of
wine, broad beans, ring C
black grapes, apricots, ∙ Ortho-dihydroxylated ring B
and strawberries (3ʹ and 4ʹ-OH groups)
∙ Chiral center at C2 and C3
with 3-OH group on ring C
∙ Meta-dihydroxylated ring A
(5- and 7-OH groups)

122–124
2 Epigallo Green tea. Tea: green, ∙ Ring B linked at position 2 of
catechin white, oolong, and ring C
gallate black teas. Fruits: ∙ Vicinal-trihydroxylated ring B
cranberries, (3ʹ, 4ʹ, and 5ʹ-OH groups)
strawberries, ∙ Chiral center at C2 and C3
blackberries, kiwis, with 3-gallate ester group on
cherries, pears, ring C
peaches, apples, and ∙ Meta-dihydroxylated ring A
avocados. Nuts: (5- and 7-OH groups)
pecans, pistachios,
and hazelnuts

(Continues)
SHARMA et al.
 SHARMA et al.

TA B L E 1 (Continued)
S. No Flavonoid Source/s Chemical structures from pubchem Structural features Reference
Isoflavone
125,126
1 Genistein Lupin, fava beans, ∙ Ring B linked at position 3 of
soybeans, kudzu, and ring C
psoralea being the ∙ Mono-hydroxylated ring B
primary food source, (4ʹ-OH group)
also in the medicinal ∙ C2 =C3 bond and 4-oxo group
plants, on ring C
Flemingiavestita and ∙ Meta-dihydroxylated ring A
F. macrophylla, and (5- and 7-OH groups)
coffee
127,128
2 Glycitein Soybeans (Glycine max), ∙ Ring B linked at position 3 of
soy flour and germ ring C
contain ∼10% and 40% ∙ Mono-hydroxylated ring B
of all soybeans (4ʹ-OH group)
isoflavones. Roots of ∙ C2 =C3 and 4-oxo group on
Pueraria (Radix ring C
puerariae) ∙ 7-OH and 5-OCH3 groups ring
A

129
3 Daidzein ∙ Ring B linked at position 3 of
ring C
∙ Mono-hydroxylated ring B
(4ʹ-OH group)
∙ C2 =C3 bond and 4-oxo group
on ring C
∙ Mono-hydroxylated ring A
(7-OH group)

(Continues)
7
 8

TA B L E 1 (Continued)
S. No Flavonoid Source/s Chemical structures from pubchem Structural features Reference
130
4 Puerarin ∙ Ring B linked at position 3 of
ring C
∙ Mono-hydroxylated ring B
(4ʹ-OH group)
∙ C2 =C3 bond and 4-oxo group
on ring C
∙ 7-OH and 8-C-glucoside
groups on ring A

131,132
5 Ononin ∙ 4’-Methoxyisoflavone and is
attached to
beta-D-glucopyranosyl moiety
at position 7 via a glycosidic
linkage
∙ It is a member of
4’-methoxyisoflavones and a
7-hydroxyisoflavones
7-O-beta-D-glucoside

(Continues)
SHARMA et al.
TA B L E 1 (Continued)
SHARMA et al.

S. No Flavonoid Source/s Chemical structures from pubchem Structural features Reference

Anthocyanidin
133,134
1 Cyanidin Red-colored berries such ∙ Ring B linked at position 2 of
as bilberry, blackberry, ring C
blueberry, cherry, ∙ Ortho-dihydroxylated ring B
cranberry, elderberry, (3ʹ and 4ʹ-OH groups)
hawthorn, loganberry, ∙ Pyrylium as ring C with 3-OH
and raspeberry, but group
also in other fruits ∙ Meta-dihydroxylated ring A
including apples, (5- and 7-OH groups)
pears, peaches, and
plums

135,136
2 Peonidin Raw cranberries, ∙ Ring B linked at position 2 of
blueberries, plums, ring C
grapes, and cherries ∙ 3ʹ-OCH3 and 4ʹ-OH groups on
ring B
∙ Pyrylium as ring C with 3-OH
group
∙ Meta-dihydroxylated ring A
(5- and 7-OH groups)

137–139
3 Apigenidin Found in sorghum, ∙ Ring B linked at position 2 of
soybean ring C
∙ Mono-hydroxlated ring B
(4ʹ-OH group)
∙ Pyrylium as ring C
∙ Meta-dihydroxylated ring A
(5- and 7-OH groups)
9
10
FIGURE 2 Mechanistic representation of flavonoids as protective agents against viral diseases
exhibiting inhibitory activity against H1N1 influenza
virus.30 This activity was observed upon substitution of
its B ring with bromine atoms. The same holds true for
its analogs as well. Precisely, baicalein interferes with the
replication ability of the influenza H5N1 virus.24 In fact,
baicalein tablets could be effectively used for the treat-
ment of acute, chronic, or persistent hepatitis, given to
their safety, compatibility, and being well tolerated.31,32
Baicalein has also been reported to exert its anti-influenza
action via restriction of NS1 protein function through
which the initiation of interferon (IFN) gets downregu-
lated. IFN-c in human CD4+ T cells and CD8+ T cells gets
induced as a result, hence baicalein acts as a best proba-
ble inducer of IFN-c during influenza virus infection.33,34
In another study, baicalein was reported to significantly
reduce the levels of human cytomegalovirus. Moreover,
same molecule had an inhibitory role in the viral DNA
synthesis despite having no effects on viral polymerase.35
Baicalein was also found to inhibit neuraminidase activ-
ity having a pronounced effect on avian influenza H5N1
virus replication.36 Baicalein also displayed anti-influenza
activity by controlling the function of NS1 protein that
downregulates IFN induction.37 In silico studies revealed
that baicalein had strong binding affinity with DENV
SHARMA et al.
NS3/NS2B protein (−7.5 kcal/mol), and may interact
closely with the virus NS5 protein at a binding affinity of
−8.6 kcal/mol.38
4.3 Quercetin
Quercetin is a flavonol that has been reported for its
antiviral activity, as established through the protection
imparted by the flavanol upon oral treatment for lethal
mengo virus in mice. Moreover, enhanced protection
was observed with the combinational administration of
quercetin with murine type I IFN.39–42 Quercetin has
been proven to exhibit a dose-dependent antiviral activ-
ity against poliovirus type 1, HSV-1, HSV-2, and respiratory
syncytial virus (RSV) in cell cultures.43 The in silico analy-
sis has revealed quercetin to be a probable inhibitor of the
neuraminidase of influenza A H1N1 and H7N9 viruses.44,45
In a study, it has been shown that quercetin triggered
a concentration-dependent decrease in the infectivity of
virus, and the intracellular replication was significantly
reduced.46 Quercetin has the capability of inhibiting HCV
infection, facilitated by the inhibition of HCVNS3 catalytic
activity of HCV RNA replicon cell system.47 The same
SHARMA et al.
compound showed significant decrease in the replication
of the viral genome. Overall, quercetin has been well
established for its dose-dependent antiviral activity against
poliovirus type 1, herpes simplex virus (HSV-1, HSV-2),
and RSV in cell cultures.48 It also exerts antirhinoviral
effects by inhibiting endocytosis, transcription of the viral
genome, and viral protein synthesis.49
Similarly, silymarin, a mixture of flavonolignans inhib-
ited the replication and emission of HCV. The RNA repli-
cation and production of viral proteins were significantly
inhibited as a result. Moreover, cell-to-cell movement of
the virus was also blocked significantly.50,51
4.4 Other flavonoids
Another flavonol, quercetagetin derived from Embeliaribes
plant extract, has been shown to have antiviral activ-
ity against HCV. As this flavonoid works as a probable
inhibitor for NS3 protease activity, it was also reported to
suppress the HCV RNA synthesis and HCV replication as
well.52
Kaempferol, another flavonol extracted from diverse
type of medicinal herbs along with its acyl substituents
and derivatives, has been shown to exhibit inhibitory
effects against HCMV.53,54 In fact, kaempferol with rham-
nose residue has been demonstrated to be the best prob-
able inhibitor of coronavirus, which has a specific effect
on 3a channel, that has involvement in the virus release
mechanism.55
Some other flavonols such as rutin, which is another
form of glycoside rutin, have been proven to have substan-
tial activity against diverse HIV-1 isolates.56,57 Rutinis, a
lycoside flavonol of quercetin was found to have antiviral
properties against EV-A71 as established through in vitro
studies in which this flavonol compound was tested against
EV-A71 strain CMUH01 (B5), displaying inhibitory effects
on the replication with an IC50 value of 110 μM. While
another study also showed its inhibitory effects by reduc-
ing the infectivity of the C4 subgenotype EV-A71 with an
IC50 value of 200 μM.58
Similarly, catechin, a flavan molecule has been reported
to be a target for influenza virus. In particular, the tea
catechins, epigallocatechin gallate (EGCG), have the abil-
ity to bind to the influenza virus (hemagglutinin), fur-
ther inhibiting its adsorption to Madin–Darby canine kid-
ney cells.59,60 EGCG has also properties that are capable
of damaging the physical properties of the viral envelope.
Moreover, it has an association with sialic acid so as to
bind to influenza A virus, further blocking the primary
low-affinity attachment to cells. Similar effects have also
been exerted on the acidification of endosomes and lyso-
somes hindering the viral entry.26,61,62 EGCG was also rec-
11
ognized to be a potent antiviral agent against Zika virus
(ZIKV), which affects the association of virus particle on
the target cell. Myricetin has also been reported to exhibit
inhibitory effects on ZIKV.63 Catechins along with deriva-
tives have been considered as probable targets in different
viruses. This was reported to have an inhibitory effect on
the acidification of endosomes and lysosomes, which may
reduce the viral entry via clathrin-mediated endocytosis.
The tea catechins revealed a significant role of its 3-gallolyl
group for antiviral activity.64,65
Catechins along with naringenin (NAR) limit virus
assembly, which gradually reduces the infectivity of
HCV.66 NAR was shown to have antidengue virus activity
as observed in A549 cells infected with ZIKV, which upon
treatment with NAR resulted in a cytopathic effect. The
concentration-dependent anti-ZIKV activity of NAR was
observed with reduced levels of virus production.67
NAR was capable of reducing the levels of replica-
tion in some strains of viruses including neurovirulent
strain of Sindbis virus. Moreover, the compound was able
to block the assembly of intracellular HCV particles.68,69
Hesperetin, another cholesterol-lowering flavanone that
is present abundantly in citrus fruits, has been known to
interfere in the virus intracellular replication displaying
pronounced anti-chikungunya (anti-CHIKV) effect. This
was further affirmed by the molecular docking studies as
evident from the interactions between hesperetin and nsP3
protein, signifying that these proteins may be a target of
hesperetin’s anti-CHIKV activity.70
Other studies affirmed that tea catechins could have
antiviral effects against HIV infection as they have the best
binding affinity to CD4 molecules present in the envelope
protein of HIV-1.71,72 Hence, catechin could contain the
viral infection but the replication of RSV and HSV-1 was
not inhibited. Moreover, catechins had negligible effects
on other viruses as well.46 Naringin was reported to have
the neutral effects on infectivity and the replication pro-
cess of any of the viruses (HSV-1, polio-virus type 1, parain-
fluenza virus type 3, RSV).46 Genistein (a tyrosine kinase
inhibitor), another flavan compound has the capability to
reduce bovine herpesvirus type 1.73 Other studies reported
that genistein could inhibit the HIV infection via interfer-
ing with HIV-mediated actin dynamics.26,74,75 Thus, genis-
tein, being a tyrosine kinase inhibitor was shown to have
antiviral effects against arenaviruses and filoviruses by
inhibiting or slowing down the replication, which could
also be possible by avoiding the phosphorylation of viral
proteins.76 Moreover, genistein also has the ability to block
proteins and thus having pronounced antiviral effects on
the replication of HSV-1 and HSV-2.77,78
Another flavonoid, gallic acid, has also been found to be
effective against HCV. Similarly, diosmetin and apigenin
have shown reduced levels of HCV infection.79 Another
12
compound, fisetin, also has an antiviral activity against
DENV-2 (daidzein in dengue virus type 2) replication.
Moreover, it also showed adequate inhibitory activity on
DENV2 and DENV3 proteases.80
Upon administration of flavonoid compounds,
quercetin and its derivatives (such as catechin, epi-
catechin, epicatechingallate, and epigallocatechingallate),
significant inhibition of SARS-3CLpro enzyme was
observed.81,82 In another study, the proteolytic activity
of SARS-CoV 3CLpro was reported to be inhibited by
deterring 3C-like protease (3CLpro) using flavonoid com-
pounds. Library of flavonoid compounds was screened to
investigate the inhibitory compounds against SARS-CoV
3CLpro.The flavonoids herbacetin, pectolinarin, and
rhoifolin were found to block the enzymatic activity of
SARS-CoV 3CLpro significantly. Flavonoid binding in the
study was validated using tryptophan-based fluorescence
method, while induced fit docking study was employed
in order to investigate the interaction of the catalytic
site of the target protein along with the binding affinity
around the S1 and S2 sites. The study further suggested
that the combination of biochemical assays and docking
studies might lead us to have useful inhibitory flavonoid
products against SARS-CoV from various flavonoid
scaffolds.16,26
Luteolin was shown to exert antiviral effect by blocking
clade B- and C-Tat-driven LTR transactivation. Also, sig-
nificant suppression in the activities of the genes Zta and
Rta was observed through the deregulation of transcription
factor Sp1 binding.83
Kaempferol along with its derivatives have also been
shown to exhibit inhibitory activity against HCMV, HSV-
1, and HSV-2 as well. Kaempferol derivatives with rham-
nose residue turned out to be potent inhibitors of the 3a
channel of coronavirus, which is involved in the mech-
anism of virus release.84,85 In an in vitro study, the
kaempferol 3-O-α-L-rhamnopyranoside derived from Zan-
thoxylum piperitum has shown significant replication inhi-
bition of influenza A virus.86
Fisetin, another flavonoid, was also known to exhibit
antiviral properties as evident from its ability to inhibit the
viral recombinant 3C protease activity. The study reported
that this molecule displayed best antiviral activity against
clinical isolate EV-A71 CMUH01 with an IC50 value of
84.5 μM.58
Similarly formononetin was shown to exhibit an
inhibitory effect on EV-A71 strains G082, SH12-036, SH12-
276 and C4 in 239S cells.87–89 Through MAPK pathway,
formononetin was able to activate downstream infection-
induced inflammatory mediators PEG2 and COX2. For-
mononetin was also reported to reduce the viral load by
suppressing the signaling cascade of the ERK, p38, and
JNK pathways to bring down the infection.89
SHARMA et al.
Hydroxyflavones are another category of synthesized
molecules with inhibitory activity against 3C protease
of EV-A71. Same group of researchers reported that
7-hydroxyflavone and di-isopropyl-flavon7-yl phosphate
inhibited virus-induced cytopathic effect in RD cells with
IC50 values of 23.45 and 13.63 μM, respectively. In addition,
both the flavonoids significantly reduced viral protein syn-
thesis as well.88
Prunin, a flavanone glycoside, has been shown to have
antiviral activity especially against enteroviruses A and B,
strains of H, B5 and C4 genotypes of EV-A71 by disrupting
viral protein and RNA synthesis.90
Another study reported the inhibitory role of pend-
uletin, a methylated flavonol against EV-A71 strain GZ-08-
02. This methylated flavonol was found to inhibit the pro-
duction of infectious RNA viral progeny.91 Another study
reported that peracetate pulicarine, a flavonoid, exhibited
anti-EV-A71 activity in initial screening results, indicating
its putative role in antiviral replication.92
5 STRUCTURE–FUNCTION
RELATIONSHIP
Flavonoids are considered to be promising natural com-
pounds proven to be active against viral infections. There
are hundreds of modern drugs that are based on the active
compounds isolated from plants, including flavonoids,
lignans, phytoalexins, tannins, and so forth, having a
diversity of functional characteristics. Basically, flavonoids
consist of 15 carbon C6 -C3 -C6 skeleton nucleus (two ben-
zene rings A and B linked through a pyrane heterocylic
ring C). The structural features of flavonoids are very
important as they superintend the biochemical, pharma-
cological activities, and biopharmaceutical properties. The
innumerable structural features are liable for targeted
biological and pharmacological effects in the organism
such as (i) conjugation between ring B and C means the
ring B is attached either at 2 or 3 position of ring C;
and (ii) number and substitution pattern of OH group
on either ring A or B. Various substitution patterns
have been observed in ring B, such as mono hydroxy-
lation, ortho-dihydroxylation, meta-dihydroxylation, and
vicinal-trihydroxylation, while the presence of meta-
dihydroxylation and vicinal-trihydroxylation are seen in
ring A; and (iii) the presence of 3-OH/3-galloyl esters/4-
oxo group/double bond between or chiral center at 2 and 3
positions of ring C. The methylated and glycoside deriva-
tives of flavonoids have been reported to widely exist in
nature possessing significant biochemical and pharma-
cological effects.6 The structural features and sources of
major flavonoid compounds possessing significant antivi-
ral properties have been summarized in Table 1.
SHARMA et al.
6 MECHANISM OF
FLAVONOID-INDUCED INHIBITION OF
CORONAVIRUS
Flavonoids have been shown to have potential
inhibitory activity against various viruses including
coronaviruses.93,94 Flavonoids can demonstrate potential
inhibitory activity against SARS-CoV-2 by binding to
essential viral targets required in virus entry and/or
replication.93 A recent report highlighted that flavonoids,
in particular quercetin and luteolin, can exhibit promising
multitarget activity against SARS-CoV-2.93,95 Flavonoids
have been shown to have potential inhibitory activity
against important viral targets that helps in their entry
and replication, including Mpro, RBD of the S protein,
RdRp, in addition to the human ACE-2 receptor and
TMPRSS2.93 Also, flavonoids have immune modulatory
effects through the inhibition of various proinflamma-
tory cytokines and pathways involved in inflammatory
reactions.93 The main protease enzyme 3C-like-protease
(3CLpro) from severe acute respiratory syndrome coro-
navirus 2 (SARS-CoV-2) is one of the important targets
to find antiviral agents.95 Some flavonoids are known
to have inhibitory effects on 3CLpro from SARS-CoV,
the causative agent of SARS. In a similar way, baicalein,
herbacetin, and pectolinarin have been found to block the
proteolytic activity of SARS-CoV-2 3CLpro.95 Baicalein
showed an effective inhibitory activity against 3CLpro of
SARS-CoV-2, and its docking mode was different from
those of herbacetin and pectolinarin.95 The investigation
suggested the important scaffolds for designing 3CLpro
inhibitors to develop antiviral agents or health foods and
dietary supplements to cope with SARS-CoV-2.95 The
3CLpro is important in the viral cycle and it is an attrac-
tive target for the development of new drugs directed
against coronavirus infection.94 It has been suggested
that dietary intervention may have improved COVID-19
outcomes and the polyphenols/flavonoids can contribute
by reducing inflammation and blocking nuclear NF-κB
translocation.94,96 The functional foods and nutraceuticals
have broad potential for preventing the mechanisms of
viral infection and modulating immune responses.94,97
Plants are rich sources of flavonoids and their worldwide
existence may prove helpful in prevention of COVID-19
after more elaborated research and clinical evidences.
7 CHALLENGES AHEAD
Implying the flavonoids as a therapeutic option in a clini-
cal perspective still is a challenge before the scientific com-
13
munity as not enough studies have been done on availabil-
ity of the bioactive component at the target site.98 More-
over, how various factors, biochemical and physiological
reactions influence the absorption and bioavailability of
flavonoids in humans, are also required to be investigated
in order to further develop these compounds to antiviral
drugs.99–104 Switching in the site of absorption of modified
hesperetin-7-glucoside from large intestine to small intes-
tine in order to enhance bioavailability of hesperetin, has
been successfully tried in the past yielding fruitful results
with enhanced plasma levels of hesperetin.105,106
8 CONCLUSIONS AND FUTURE
PERSPECTIVES
Natural products are the mainstay for developing antiviral
drugs because of their ease of availability and lesser num-
ber of side effects. Dietary flavonoids are abundantly avail-
able in fruits, vegetables, tea, and so forth, making them a
viable therapeutic option against variety of viral diseases,
including coronavirus disease as evidenced through num-
ber of in vitro studies. However, we require large cohorts of
randomized controlled in vivo and clinical research stud-
ies in order to replicate the in vitro findings and to gain
insight into the mechanism of action of such flavonoids
having wide-spectrum therapeutic potential. Understand-
ing of the complex biochemical and pharmacokinetic path-
ways anticipated to be influenced by flavonoids would cer-
tainly pave a way for developing them as future antiviral
therapeutics.
AC K N OW L E D G M E N T S
We greatly acknowledge Maharishi Markandeshwar
(deemed to be University) Mullana (Ambala), Haryana,
India for providing the requisite platform for this work.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest
regarding this manuscript.
ORCID
Anil K. Sharma https://orcid.org/0000-0002-9768-1644
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How to cite this article: Sharma V, Sehrawat N,
Sharma A, Yadav M, Verma P, Sharma AK.
Multifaceted antiviral therapeutic potential of
dietary flavonoids: Emerging trends and future
perspectives. Biotechnol Appl Biochem. 2021;1–18.
https://doi.org/10.1002/bab.2265