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76 Flavonoids as Nutraceuticals
4.2.3 TARGETING HOST MACHINERY EXPLOITED BY VIRUSES
The interplay between virus and host determines viral infection resistance
and recovery. The host’s defenses may act directly and indirectly on virus
reproduction by modifying or killing the infected cell. Non-specific host
defenses work early in the virus encounter to avoid or restrict infection,
whereas specific host defenses work after infection to restore immunity or
develop memory cells for future threats.
Cellular metabolism is one factor that is increasingly recognized for
virus-host interactions. Nowadays, viruses' co-existence with their host can
be viewed as a molecular race between the virus and the host elimination
mechanism. Continued interaction between the host and pathogen during
their co-evolution has shaped the immune system. In turn, the viruses have
manipulated the host control mechanism to facilitate their own replication,
transcription, and translation. This chapter investigates how host cell meta
-
bolic pathways are imitated, exploited, or disrupted by different classes of
viruses to bypass/escape immune responses. This includes a brief synopsis
of the virus's introduction to the signaling pathways and examples of the
virus’s strategies for controlling the host cell metabolic activities.
The inter-related pathways studied for their signicant role in viral infec-
tion are glycolysis, Krebs cycle, pentose phosphate pathway, β-oxidation,
amino-acid and fatty acid synthesis pathway, and the host immune systems.
T. Murayama studied in 1998 that the production of interleukin 8 (IL-8)
during HCMV infection increased infectious viral replication. They conclude
that the progression of HCMV infection is linked to the virus replication
and the host immune system (Murayama, 1998). While Munger et al. rst
characterized the effect of HCMV-infected cells in the host metabolic envi-
ronment, concluding that the levels of several metabolic pathways, such
as the Krebs cycle, as the infection progresses glycolysis and amino acids
biosynthesis, upsurge. They evaluated 63 different intracellular metabolites
during infection compared to normal broblast development, indicating
that the virally infected cells considerably impacted metabolic homeostasis
(Munger et al., 2006). Viruses such as HCV, DENV, HSV 1, HIV-1, rubella
virus, rhinovirus, inuenza virus, adenovirus, and CoV have been shown to
initiate a host cell response characterized by an elevated level of glucose,
resulting in a hospitable intracellular environment for viral replication and
inammatory cytokine expression (Codo et al., 2020; Deng et al., 2011;
Fischl & Bartenschlager, 2011; Lee et al., 2020; Logette et al., 2021; Loisel-
Meyer et al., 2012; Prusinkiewicz et al., 2020; Bilz et al., 2018; Ren et al.,
2021; Vafeiadou et al., 2009; Weng et al., 2021; Wu et al., 2020). Nowadays,
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77 Therapeutic Antiviral Potential of Flavonoids
several viruses have been demonstrated to disrupt numerous major metabolic
pathways, and the number of signaling pathways has been examined (Du et
al., 2021;
Birungi et al., 2010; Gou et al., 2021; Lin et al., 2010; Manchester
& Anand, 2017; Romagnolo & Carvalho, 2021; Xu et al., 2021).
Mitochondria are vital organelles that generate adenosine triphosphate
(ATP) via oxidative phosphorylation and govern cell cycle and differentia
-
tion, manage calcium signaling, and generate reactive oxygen species (ROS)
(Wallace, 2012). The mitochondria are directly targeted by viral proteins or
impacted by physiological modications to the cellular environment, such
as disrupted calcium homeostasis, endoplasmic reticulum stress, oxidative
stress, and hypoxia during viral pathogenesis. An example of this virus-
mitochondria interaction is the blocking of mitochondria-associated antiviral
signaling. Khan et al. revealed that HBV and HCV promote mitophagy
and mitochondrial ssion, downregulating apoptosis and boosting viral
persistence (Kim et al., 2014). Kaposi’s sarcoma-associated herpesvirus
(KSHV) encodes microRNAs that have a detrimental inuence on mito
-
chondrial biogenesis and function, perhaps through an interaction with the
heat shock proteins. However, it is unclear how and why KSHV affects
host cell metabolism (Yogev et al., 2014). The HCMV protein also affects
the reticular mitochondrial network and inhibits apoptotic signals in mito-
chondria. It directly suppresses apoptotic signaling pathways by interfering
with the mitochondria-localized inhibitor of apoptosis and viral inhibitor of
caspase-8-induced apoptosis proteins (Goldmacher, 2005). However, how
viral proteins that target mitochondrial dynamics affect core mitochondrial
metabolic activity is poorly unknown. Further research into the involvement
of mitochondrial dynamics in viral infection will help us better understand
virus-host interaction and their signicance in pathogenesis.
Other than these metabolic processes, viruses also aim for polyamine
pathways. Polyamines are positively charged small molecules found in
all cells. Cellular functions such as nucleic acid binding, cell cycle, and
membrane uidity are all affected by polyamine levels in the cells (Frugier
et al., 1994). Gibson et al.'s studies have revealed that viral capsids of
herpesvirus include substantial quantities of polyamines, which are thought
to neutralize charges on viral DNA to aid compaction and encapsidation
(Gibson & Roizman, 1971). Bacteriophage R17 (Fukuma & Cohen, 1975)
and Vaccinia virus (Lanzer & Holowczak, 1975) also incorporate polyamine
into virions. According to Mounce et al., polyamines are necessary for both
the transcription and translation of RNA viruses, i.e., CHIKV and ZIKV.
They demonstrated that CHIKV and ZIKV replication is restricted when
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78 Flavonoids as Nutraceuticals
polyamines are depleted via type I interferon signaling-mediated activation
of spermidine/spermine N1-acetyltransferase (SAT1) (Mounce et al., 2016).
In vivo studies in mice, Drosophila melanogaster, and zebrash showed
that polyamines are necessary for efcient viral replication in multiple hosts
(Mounce et al., 2016). So, the potential role of polyamines in virus replica-
tion for a broader range of RNA viruses highlights as a promising drug target.
Similarly, some studies show the crucial role of avonoids against these
viruses by shielding the host cell factors. Reid et al. in 2014 show ER chaperon
(HSPA5) inhibitor EGCG play a protective role against the Ebola virus (Reid
et al., 2014). Moreover, naringenin inhibits HCV production mediated by the
activation of peroxisome proliferator-activated receptor (PPARα), resulting
in a decrease in very-low-density lipoprotein production (
Goldwasser et al.,
2011). Furthermore, Wang et al.'s studies showed the role of avopiridol in
inhibiting viral replication. They conclude that the host RNA polymerase
activity is inhibited by avopiridol, ,which causes a decrease in viral mRNA
production (Wang et al., 2012). A few examples of viruses that target the
different host target by various viruses are given in Table 4.14.
TABLE 4.14 Different Host Pathways Targeted by Viruses
Pathways Virus In Vitro/ References
In Vivo
Glycolytic
pathway
Mitochondrial
pathway
KSHV
HCMV
Adenovirus
EBV
DENV
HCV
Influenza A
HSV-1
KSHV
HCV
Hepatitis B
HCMV
Classical swine
fever virus (CSFV)
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
Yogev et al. (2014)
Munger et al. (2008); Vastag et al. (2011)
Thai et al. (2014)
Xu et al. (2014)
Fontaine et al. (2015); Lee et al. (2020);
Romagnolo & Carvalho (2021)
Ramière et al. (2014); Deng et al. (2011); Shoji
et al. (2015)
Munger et al. (2008); Ren et al. (2021)
Vastag et al. (2011)
Yogev et al. (2014)
Kim et al. (2014)
Kim et al. (2013)
Arnoult et al. (2004); Goldmacher (2005);
Pauleau et al. (2007)
Gou et al. (2017)
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79 Therapeutic Antiviral Potential of Flavonoids
TABLE 4.14 (Continued)
Pathways Virus In Vitro/
In Vivo
References
TCA cycle HCMV
In vitro
Munger et al. (2008); Spencer et al. (2011);
Vastag et al. (2011)
HSV-1
In vitro
Vastag et al. (2011)
Lipid
metabolism
Hepatitis C
In vitro
Filipe & McLauchlan (2015); Herker et al.
(2010);
Hofmann et al. (2018); Lee et al. (2019);
Romagnolo & Carvalho (2021); Vieyres &
Pietschmann (2019)
DENV
In vitro
Cloherty et al. (2020); Romagnolo & Carvalho
(2021); Samsa et al. (2009); Zhang et al. (2018)
ZIKV
In vitro
Cloherty et al. (2020)
Fatty acid
synthesis
pathway.
HCMV
CSFV
DENV
In vitro
In vitro
In vitro
Munger et al. (2008); Purdy et al. (2015)
Liu et al. (2021)
Tang et al. (2014)
Polyamine
pathway
HSV
CHIKV
In vitro
In vitro
and in
Gibson & Roizman (1971)
Mounce et al. (2016, 2017)
vivo
CV B3
In vitro
Dial et al. (2019); Hulsebosch & Mounce (2021);
Kicmal et al. (2019)
ZIKV
In vitro
and in
Mounce et al. (2016); Routhu et al. (2018)
vivo
Bunyavirus
In vitro
Mastrodomenico et al. (2019)
SARS-CoV-2
In vitro
Firpo et al. (2021)
4.3 STRUCTURE-BASED STUDY OF FLAVANOIDS AGAINST
VARIOUS VIRUSES
Structure-based drug design is becoming a crucial tool for faster and more
cost-efficient lead discovery than the conventional method (Aggarwal et al.,
2014, 2015, 2017; Fatma et al., 2020; Kumar et al., 2021; Sharma et al.,
2016, 2018). Structural studies have provided a plethora of new targets and
opportunities for future drug discovery against viruses (Saha et al., 2018;
Kumar et al., 2021; Narwal et al., 2018; Rani et al., 2020; Choudhary et
al., 2020; Singh et al., 2018). Experimental high-throughput screening
is time-consuming and expensive. Hence, it is essential to overcome the
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80 Flavonoids as Nutraceuticals
boundaries of the conventional drug discovery methods with efficient, low-
cost, and broad-spectrum computational alternatives. Here, some examples
of structure-based flavonoid drug discovery have been given, which can be
used as potential therapeutics.
Human papillomavirus (HPV) is a dsDNA virus from the Papovaviridae
family. Early protein 6 (E6) has a vital role in replication and oncogenesis in
cervical cancers. The new class of luteolin disrupts the E6/E6AP interaction.
Hence, these compounds may play a role in developing antiviral therapy in
treating HPV infection and cervical cancer (
Cherry et al., 2013). In silico
study of 5,7,40-Trihydroxy-30-methoxy avone inhibits Rhinovirus (HRV)
entry inhibition by binding to the HRV protein grid (Kant et al.).
Similarly, Silymarin interacts with the binding pocket of DENV nsP4B,
including potential antiviral activity against DENV (Qaddir et al., 2017).
Puranik et al. studied the halogenated dihydro-rugosa avonoids against
non-structural protein 3 (nsP3) protein of CHIKV, which shows antiviral
activity based on the in in-silico as well as in in vitro studies (Puranik et al.,
2019). Coumarin, Coumestan, and Neoavone derivatives have shown inter-
action with HCV NS5B Polymerase, indicating potential antiviral activity
(Nichols et al., 2013;
Kaushik et al., 2008). Tripathi et al. investigated the
role of naringin avanoid against CHIKV nsP2. They found that the struc
-
tural changes in nsP2 caused by naringin binding are expected to disrupt
the enzyme’s normal activity during the CHIKV viral life cycle (Tripathi et
al., 2020). Despite the fact that the ZIKV is a well-known and widespread
pandemic. Furthermore, Catoline et al. presented the pedalitin avanoid as a
possibility for hit-to-lead (H2L) optimization studies for antiviral candidates
against ZIKV infections (Lima et al., 2021). In addition, citrus avanone
naringenin showed antiviral action against ZIKV in in-silico and in-vitro
studies, suggesting that it inhibits viral reproduction or its assembly (Cataneo
et al., 2019).
In silico docking study revealed that the herbacetin and pectolinarin
interact with the domain of severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) main protease (3CLpro), indicating that it has antiviral
potential. The research provides crucial scaffolds for developing 3CLpro
inhibitors as antiviral to combat SARS-CoV-2 infection (Jo et al., 2020).
Susmit et al. studied several SARS-CoV-2 proteins involved in viral
replication, transcription, and translation as potential therapeutic targets.
In a docking investigation against 3Clpro, spike receptor-binding domain
(RBD), nsp3 (PLpro), nsp12 (RNA dependent RNA polymerase; RdRp), and
Angiotensin-converting enzyme 2 (ACE2) receptor, EGCG and theaavin
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Therapeutic Antiviral Potential of Flavonoids 81
digallate showed excellent binding against all the proteins of virus (Jang
et al., 2021; Mhatre et al., 2021). In a similar study, researchers showed
that EGCG forms favorable interactions with the spike protein and can
potentially impair the function of the SARS-CoV-2 UK variant (Mhatre et
al., 2021). Mohmoud et al. tested a database of 2017 avone compounds
against SARS-CoV-2 Mpro virtually. Based on the docking scores, they
discovered rutin’s dynamics and energetics against SARS-CoV-2, which
may be investigated in vitro and in vivo to combat the epidemic (Ibrahim et
al., 2021). In vitro investigations against SARS-CoV-2 showed that baicalein
and baicalin have considerable antiviral efcacy. Furthermore, cell-based
and biochemical investigations revealed that both drugs directly block the
function of SARS-CoV-2 RdRp (Zandi et al., 2021). Quercetin and its seleno
functionalized derivative (8-(p-tolylselenyl) quercetin) blocks SARS-CoV-2
replication in virus-infected cells by inhibiting Mpro. Moreover, Seleno
derivation increases Mpro activity by forming a hydrogen bond among the
selenium atom and Gln189 residue in the catalytic pocket. Similarly, Rutin,
a glycosylated conjugate of quercetin, increases bioavailability at low micro-
molar concentrations (Rizzuti et al., 2021).
The principles and methods discussed here highlight the strategies in
silico approaches that have been applied to identify avonoid compounds as
antivirals. Undoubtedly, challenges remain to show antiviral activity. Never-
theless, in the current scenario, structure-based drug identication has a
crucial role in drug discovery. As shown in the above studies, structure-based
drug identication has been able to identify promising avonoid compounds
that might represent future solutions in critical areas of antivirals.
4.4 CLINICAL STUDIES OF FLAVANOIDS AGAINST VARIOUS
VIRUSES
Clinical trials research studies new tests and treatments and assesses their
effects on human health outcomes. There are four phases in which people
volunteer to participate in clinical trials to test medical interventions. Flavo-
noids have been used to treat virus infections in clinical trials few of the trials
have been mentioned below.
Clinical trials have shown that Gene-Eden-VIR/Novirin is a safe and
effective treatment against many viruses, including HCV, HPV, HCMV,
HSV, and EBV (Polansky et al., 2016, 2017, 2018; Polansky & Itzkovitz,
2013). In the Phase II Clinical trial, intravenously injection of Silibinin
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82 Flavonoids as Nutraceuticals
in HCV-infected pegylated interferon/ribavirin therapy non-responders
have shown potent antiviral activity. It has been postulated that silibinin's
antiviral activity is facilitated by immune-mediated IFN-JAK/STAT inde
-
pendent antiviral mechanisms by regulating Toll-like receptor 7, interferon
regulatory factor 3, and p38 protein kinase pathways (
Ferenci et al., 2008).
Silibinin monotherapy has effective antiviral activity in established HCV
recurrence patients where the graft is not responding to standard therapy and
conrms the therapy has high safety and tolerability without interaction with
immunosuppressive drugs (Rendina et al., 2014).
4.5 CONCLUSION
Since the beginning, viral infections have affected the whole ecosystem.
The present scenario reiterates that viral disease spreads worldwide rapidly.
Pandemics and epidemics caused by these virus infections influence billions
of lives directly and indirectly. Drug discovery itself is a challenging and
time-consuming job. Structure-based studies have an essential role in the
process of identifying novel molecules and postulating interactions. Various
flavonoids have shown antiviral activity via manipulating host as well as
viral factors.
Furthermore, clinical trials are helping researchers to understand the
avonoids impact on human health. As synthetic antiviral molecules usually
have limited efcacy due to their substantial side effects. Overall, naturally
occurring avonoids in the diet can be seen as a beacon of hope.
KEYWORDS
• antiviral retroviruses
• flavonoids
• Hepadnaviridae
• molecular inhibition
• retroviruses
• RNA and DNA viruses
• ssRNA viruses
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