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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_6035_Библиотеки_им_академика_М_И_Перельмана.pdf
CHAPTER 7
Natural Products with Antiviral Properties
MARIA CAROLINA JASSO MIRANDA
ABSTRACT
Viruses are nanometric infectious particles that throughout history have caused pandemics.
The genomes of some viruses can mutate rapidly to generate highly pathogenic viral
variants; in addition, this high mutation rate favors the evasion of antiviral immune response
and development of resistance to the few antivirals currently available. There are just a few
viruses for which specific antiviral treatment is available; generally, the treatment given is
symptomatic. Scientific evidence supports that natural compounds including flavonoids
and polyphenols have the ability to inhibit the replication of viruses under different
mechanisms of action. Some of these natural compounds also possess anti-inflammatory
and antioxidant properties; and they also modulate autophagy processes by interfering
directly or indirectly with the replicative cycle of some viruses. These compounds are
derived from various sources such as plants, algae, propolis, or microorganisms. The
research of natural products in virology is very extensive as numerous novel compounds
are being discovered. Additionally, derivatives of these compounds with better activity
and less toxicity are obtained leading us to glimpse a panorama advantageous in antiviral
pharmacology. With optimism, we can predict that in the not-too-distant future, we will
have specific and not only symptomatic antiviral treatments for some viral diseases.
*
*Corresponding author
7.1 INTRODUCTION
Viruses are infectious particles that can only replicate inside a cell, since they require
hijacking the cellular machinery to replicate its genome, synthesize its proteins, and create
and secrete many virions that could infect other cells, thus repeating the cycle replicative.
Viruses are nanometric particles that are made up of nucleic acids (genome), proteins,
and sometimes lipids; there is no general shape or structure for viruses. There are viruses
that are naked while others are enveloped; some have a DNA genome and others RNA.
There are viruses with a single-stranded genome and others with double or circular strands.
134
S some viruses have icosahedral capsids while others have helical capsids; some viruses
are very small (such as picornaviruses), while other viruses are very large (such as
mimiviruses).
Viruses, despite being so small that until today they are not considered living beings,
have caused many problems for humanity. In 1918, the inuenza virus was responsible
for the death of at least 50 million people worldwide (Berche, 2022); in 2009, another
inuenza virus alerted the health authorities, estimating in this case between 105,700 and
395,600 deaths worldwide (Dawood et al., 2012). The inuenza virus is not the only virus
that has caused pandemics and the death of many people worldwide. At the beginning
of 2020, the coronavirus (SARS-CoV-2) caused a pandemic that according to the World
Health Organization until March 2023 caused at least about 7 million deaths worldwide.
There are large differences in the behavior between the pandemic by inuenza in 1918
and in 2009 due to multiple factors, including the existence of vaccines against inuenza
virus in 2009 compared to the absence of these in 1918. In addition, there were different
viral strains in populations with very different social, economic, and health situations.
While it is true that we now have scientic and technological tools that allow us to
develop vaccines relatively quickly , it is also true that viruses, and especially viruses such
as inuenza virus, could have the ability to mutate very quickly and evade the antiviral
immune system.
The high mutation rate of some viruses also facilitates the generation of resistance to the
few antivirals available in the market today. Such is the case of amantadine, an excellent
antiviral in its early days against inuenza but to which practically all currently circulating
inuenza viruses are resistant (Hussain et al., 2017). Oseltamivir and its derivatives are
relatively new drugs versus inuenza virus; however, some viral strains are already resistant
to these drugs (Govorkova, 2013; Samson et al., 2013).
In recent years, some products of natural origin have become relevant in medical
virology, since compounds have been found in plants, propolis and marine algae with
the capacity to inhibit the replication of some viruses, in addition to having some other
properties that may be benecial for the treatment of viral diseases. This chapter describes
the properties of some products or compounds of natural origin with therapeutic potential
for diseases of viral origin.
7.2 SOURCE OF NATURAL PRODUCTS WITH ANTIVIRAL ACTIVITY
Different isolated or naturally occurring products have been shown to have antiviral activity
in vitro and in vivo. Many of these products are extracts that come from plants, whether
from seeds, flowers, fruits, leaves, stems, or roots. Plants generally generate these products
as secondary metabolites, which play a very important role in adaptation to environmental
stress and in defense against potential predators and pathogens (Twaij and Hasan 2022).
Some other products with antiviral properties have been obtained from marine sources,
such as algae, while others come from the metabolism of some microorganisms such
as bacteria and fungi, which secrete this type of product to defend themselves from the
ecosystem in which they inhabit (Rosales-Mendoza et al., 2020; Raihan et al., 2021).
135
7.3 MAIN COMPONENTS OF NATURAL PRODUCTS
An extract or product obtained from nature can have different properties, including antibacterial, antifungal, antiviral, antiproliferative, and anti-inflammatory properties, among
others. One aspect to highlight is that these natural products can generally contain various
types of compounds in lesser or greater quantities. It is essential to characterize these
products and know what components they are made of to finally be able to elucidate what
compound or compounds are responsible for the properties described for each product.
Among the compounds that have been isolated and characterized from products of
natural origin that have antiviral activity, we mainly have some avonoids, polyphenols,
polysaccharides, and terpenes.
7.3.1 FLAVONOIDS
Flavonoids are a group of naturally occurring compounds for which multiple biological
activities have been described, including antioxidant, antiproliferative, antibacterial, antifungal, and antiviral properties (Friedman, 2014; Badshah et al., 2021; Dias et al., 2021;
Al-Khayri et al., 2022).
Most of the avonoids present a structure with two benzene rings connected by a heterocycle pyrene ring with oxygen. Flavonoids can be classied into anthocyanidins, avones,
avonols, isoavones, avanones, avanonols, and avan-3-ols (Dias et al., 2021). Figure 7.1
shows the structure of the major groups of avonoids.
FIGURE 7.1 Basic structure of the major types of flavonoids: (a) flavan (basic structure of flavonoids), (b)
anthocyanidins, (c) flavones, (d) flavanols, (e) isoflavones, (f) flavanones, (g) flavanonols, and (h) flavan-3-ols.
Quercetin and some of its derivatives are perhaps the avonoids with the greatest antiviral potential described to date, with evidence of their inhibitory potential against viruses
⏎
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such as dengue virus (Zandi et al., 2011), inuenza virus (Wu et al., 2015), Zika virus (Wong
et al., 2017), SARS-CoV -2 (Gasmi et al., 2022), herpes simplex virus (Kim et al., 2020), and
Japanese encephalitis virus (Johari et al., 2012) among others.
7.3.2 POLYPHENOLS
Polyphenols are molecules with one or more phenolic rings that naturally occur as
micronutrients in plants and most of them are linked to sugars (in the form of glycosides).
These compounds are the most abundant antioxidants in the diet, and they are present in
many food sources (Pandey and Rizvi, 2009). Polyphenols can be classified into groups,
according to the number of phenolic rings, the structural elements, and substituents; also,
they can be subdivided in flavonoids and nonflavonoids.
7.3.3 POLYSACCHARIDES
Some naturally occurring polysaccharides can be isolated from plants, algae, and fungi;
they play multiple roles and have extensive bioactivities. Polysaccharides can have different
structural characteristics, including the elements or substituents that make them up, all of
which have repercussions on their biological properties, including antiviral effects (Pandey
and Rizvi, 2009).
7.3.4 TERPENOIDS
Terpenoids are a large class of organic molecules found in nature, derived from isoprene,
and its polymers known as terpenes. Terpenes and terpenoids have a variety of roles in
nature, mainly protecting a lot of species of plants, animals, and microorganisms against
predators, pathogens, and competitors (Gershenzon and Dudareva, 2007).
7.4 MECHANISMS OF ACTION OF NATURAL COMPOUNDS IN VIRAL INFECTIONS
7.4.1 DIRECT ANTIVIRAL EFFECT
In-silico and in-vitro studies have shown that some naturally occurring compounds have the
potential to directly inhibit some viruses, either by binding to the viral protein that interacts
with the specific cell receptor, thus inhibiting virus entry into the cell or by inhibiting viral
enzymes that are a clue for viral genome replication or for posttranslational modification
of viral proteins. Table 7.1 includes some compounds of natural origin with antiviral
properties exerted directly on some part of the replication process of specific viruses.
The fact that some types of natural compounds such as avonoids, polyphenols, and
polysaccharides exert a direct effect on replicative cycle of some viruses allows us to see
the great potential that this type of compound has within the eld of virology, especially
TABLE 7.1 Compounds Exhibiting Direct Antiviral Activity
Compound Antiviral Activity Mechanism Virus References
Flavonoids
Quercetin Inhibited viral entry
Inhibited a viral enzyme
Inhibited a viral protease
Fisetin Inhibited viral entry SARS-CoV-2 Mishra et al. (2022)
Naringenin Inhibited viral assembly
Inhibited viral helicase
Isoquercitrin Inhibited viral polymerase Dengue virus Jarerattanachat et al. (2023)
Luteolin Inhibited viral polymerase Hepatitis C virus Manvar et al. (2012)
Licoflavone C Inhibited viral helicase SARS-CoV-2 Corona et al. (2022)
Polyphenols
Curcumin Inhibited viral entry
Inhibited a viral protease
Inhibited cell binding
Resveratrol Inhibited viral helicase Zika virus Devnarain and Soliman
Vitisin B Inhibited viral helicase Hepatitis C virus Lee
Griffithsin Inhibited viral entry Human immunodeficiency virus Emau et al. (2007)
Polysaccharides
N-(2-Hydroxypropyl)-3trimethylammonium chitosan chloride
Polysaccharide fractions isolated from
Arthrospira platensis
Carrageenan Inhibition of viral protein synthesis but not viral entry herpes simplex virus Gonzalez et al. (1987)
Terpenes
Beta-pinene and limonene Inhibited viral entry Herpes simplex virus Astani and Schnitzler (2014)
Betulinic acid Inhibited a viral protease SARS-CoV-2 Wen
Inhibited viral entry Human coronavirus HCoV-NL63 Milewska
Inhibited the herpes virus in an entry phase, but at a
stage later than virus entry inhibited HIV
⏎
Dengue virus
Influenza A virus
SARS-CoV-2
Hepatitis C virus
Zika virus
Influenza A virus
Dengue virus
Chikungunya viruses
Herpes simplex virus and human
immunodeficiency virus type 1
Mir et al. (2016)
Chintakrindi et al. (2016)
Gu et al. (2021)
Goldwasser et al. (2011)
Cataneo et al. (2019)
Richart
et al. (2018)
Balasubramanian et al. (2019)
Mounce et al. (2017)
(2019)
et al. (2016)
et al. (2016)
Rechter et al. (2006)
et al. (2007)
137
138
for most of these viral infections, there is nonspecic antiviral treatment. In many cases,
the treatment given is mainly symptomatic. In addition, the fact that these compounds can
act at different points in the replication cycle of some viruses may slightly increase the
possibility of evading the generation of antiviral resistance.
An important subject in the study of molecules with antiviral potential is the study of
derivatives polyphenolic of previously described compounds with antiviral activity; this
will open the doors to the discovery of molecules with better activities and perhaps a lower
level of toxicity . For example, curcumin is a large and symmetrical compound (Figure 7.2),
which we can chemically modify and thus obtain different derivatives that have different
properties. Balasubramanian et al. (2019) found that some derivatives of curcumin have a
greater effect against dengue virus than curcumin itself.
FIGURE 7.2 Curcumin, a symmetric polyphenolic compound with antiviral and anti-inflammatory properties.
Another important example of the study of derivatives of natural compounds with
antiviral effects was provided by Wleklik et al. (1988), who described the importance of
avonoid substituents and how they inuence the inhibitory activity against the herpes
simplex virus. In this investigation, it was discovered that the substitution of hydroxyl
groups of carbons 3, 5, 7, 3′, and 4′ decreased or completely eliminated the antiviral activity
of the avonoids studied against the herpes simplex virus. This has also been observed in
other study models, for example, quercetin and setin have good inhibitory activity against
dengue in macrophages but not apigenin or rutin (Jasso-Miranda et al. 2019), which lack
hydroxyl group at carbon 3 (Figure 7.3).
7.4.2 ANTI-INFLAMMATORY EFFECT IN VIRAL INFECTIONS
In some viral diseases, the main problem is not the viral infection as such but immunopathology present during the infectious process. One of the diseases for which immune
response plays an extremely important role is dengue, a disease that can be present in severe
forms when the inflammatory response is deregulated, presenting a phenomenon known as
“a cytokine storm” that can lead to the development of hypovolemic shock and death of the
patient. Other viral diseases in which a dysregulation of inflammatory cytokines can also
occur are COVID-19 (Montazersaheb et al., 2022) and influenza (Liu et al., 2016; Ryabkova
et al., 2021).
⏎
139
FIGURE 7.3 (a) General structure of flavonoids, (b) quercetin, (c) fisetin, (d) apigenin, and (e) rutin.
⏎
Some compounds of natural origin, in addition to having the ability to inhibit the repli-
cation of some viruses, also have anti-inammatory properties; particularly, it has been
observed that some compounds can suppress the synthesis or secretion of cytokines such
as IL-1, IL-6, and TNF-α, cytokines that are upregulated in viral diseases such as dengue,
inuenza, and COVID-19.
The fact that a compound of natural origin could inhibit the replication of some viruses
and also modulate the immune response is very important since this could help avoid the
pathology induced by the deregulation of the immune response in addition to affecting the
virus directly. Table 7.2 exemplies some compounds of natural origin with antiviral and
anti-inammatory activity in the same study model.
In some studies, it has been found that some naturally occurring compounds may have
an anti-inammatory but not an antiviral effect in certain study models. These compounds,
despite not showing an antiviral effect as such, are not completely ruled out in pharmaceutical research in virology, since, as previously mentioned, the immune response plays
a very important role in the evolution of viral diseases.
Such is the case of curcumin, a polyphenolic compound for which noninhibitory
effect was found against dengue virus in a monocytic cell line, but a very important anti-
inammatory effect was obtained with different serotypes of dengue virus (Jasso-Miranda
et al., 2019). Curiously, in other study models with other different cell lines, curcumin has
shown to have inhibitory potential against the dengue virus (Balasubramanian et al., 2019).
The above study shows the importance of further research using the most appropriate study
140
models for each type of viral infection and the subsequent study in in-vivo models where a
more complete panorama is studied.
TABLE 7.2 Some Compounds for Which Antiviral Activity and Anti-Inflammatory Effect Has Been
Described in In-Vitro Studies
Compound Virus Inhibited Effect on Immune Response References
Flavonoids
Quercetin Dengue virus
Human
metapneumovirus
SARS-CoV-2
Fisetin Dengue virus Suppress IL-6, TNF-α, and IL-10 secretion
Apigenin Influenza virus Suppress IL-6 expression Xu et al. (2020)
Polyphenols
Curcumin SARS-CoV-2 Suppress IL-1β, IL-6, and IL-8 Marín-Palma
Resveratrol Enterovirus 71 Suppress IL-6 and TNF-α secretion Zhang et al. (2015)
Polysaccharides
Radix isatidis
polysaccharides
Influenza A virus Suppress IL-6, IP-10, MIG, and CCL-5
⏎
Suppress IL-6, TNF-α, and IL-10 secretion
Suppress IL-6, TNF-α, IL-8, CCL5, IL-1α,
CXCL10, and CCL4 expression
Suppress the NLRP3 inflammasome
expression
Jasso-Miranda et al. (2019)
Komaravelli et al. (2015)
Saeedi-Boroujeni and
Mahmoudian-Sani (2021)
Jasso-Miranda et al. (2019)
et al. 2021)
Li
et al. (2017)
One of the questions that have arisen regarding the ability of some naturally occurring
compounds to regulate the inammatory response is how they carry out this activity. When
the compound can affect viral replication, and at the same time, the level of inammation,
there could be a certain relationship between one effect and another but not necessarily . On
the other hand, some studies have shown that some natural compounds can decrease the
expression and/or activation of some key transcription factors in the inammatory immune
response. Table 7.3 shows some examples.
7.4.3 EFFECT ON AUTOPHAGY PROCESS
Another possible mechanism of antiviral and anti-inflammatory action of some natural
compounds is the inhibition of autophagy. Autophagy is a process of cellular self-degradation
that allows regulating homeostasis at critical moments or cellular stress. It is a process that
may or may not be selective and allows the degradation of misfolded proteins and damaged
organelles, in addition to allowing the elimination of intracellular pathogens (Glick et al., 2010).
There is much controversy about the role of autophagy in viral infections. Autophagy
allows the elimination of intracellular pathogens to a certain extent, as is the case with
viruses; however, it has been found that some viruses can stimulate the autophagy process
and use it to their advantage (Choi et al., 2018).
One of the possible mechanisms by which autophagy can help some viruses is that
autophagosomes that are formed can function as a viral replication factory, concentrating
viral elements and giving them protection from cellular proteases and nucleases, in addition
141
to preventing these components from being detected by pattern recognition receptors that
could activate the innate immune response and possible viral degradation (Choi et al.,
2018; Mao et al., 2019).
TABLE 7.3 Mechanisms of Anti-Inflammatory Action of Some Compounds of Natural Origin
Compound Effect Anti‑Inflammatory Activity Mechanism References
Quercetin Reduced levels of
inflammatory cytokines
Resveratrol Reduced levels of
inflammatory cytokines
Curcumin Suppressed cytokine release
syndrome
Radix isatidis
polysaccharides
Reduced expression of IL-6
and IP-10, MIG, and CCL-5
Suppress factor nuclear factor (NF-κB)
and TLR signaling pathways
Inhibition of NF-κB and interferon
regulatory factor (IRF)-3
Regulated PI3K/Akt/mTOR pathway
Blocked IKKs/NF-κB signaling pathway
Blocked NF-κB, inflammasome, HMGB1,
and IL-6-driven inflammatory responses
Inhibited activation of the TLR-3
signaling pathway
⏎
Zheng
et al. (2021)
Komaravelli et al.
(2015)
Chen
et al. (2022)
Zhang et al. (2015)
Thimmulappa
et al. (2021)
Li et al. (2017)
Although there are reports that many viruses modify or manipulate the autophagy
process, it is not an effect that can be generalized to all viruses, since some can stimulate
and others can inhibit this cellular process. In fact, some viruses can activate only some
points of the autophagy process but not the entire process; such is the case of the herpes
simplex virus, which favors the formation of autophagosomes but inhibits their maturation.
This allows it to have a viral factory and a source of envelope for its virions, besides evading
the activation of the innate immune response and the destruction of viral components
(Lussignol and Esclatine, 2017).
On the other hand, there is also scientic evidence indicating that some naturally occurring compounds can modify the autophagy process, either by activating or by inhibiting
it. This property gives these compounds certain characteristics or properties, for example,
it has been related that the effect of some natural avonoids, polyphenols, and polysaccharides on autophagy inuences their anticancer capacity (Ashrazadeh et al., 2020; Pang
et al., 2021; Wu et al., 2021; Li et al., 2022).
The fact that a compound of natural origin can stimulate or suppress the autophagy process
can have a signicant impact on the replicative cycle of some viruses. Such is the case of
chrysin, a avonoid that inhibits the replication of the inuenza virus, perhaps through various
mechanisms, one of them being the inhibition of autophagy (Kim et al., 2021). Another example
is baicalein, another avonoid with an inhibitory effect on the replication of Chikungunya virus
due to an inhibitory effect on the autophagy process in addition to other factors (Oo
et al., 2018).
7.5 IN-VIVO STUDIES
As described, some naturally occurring compounds can produce different effects in-vitro
cells infected with different types of viruses; however , it is important to evaluate the ef fect
of these compounds in in-vivo models.
142
The study in in-vivo models allows us to comprehensively evaluate the effect of the
compounds in a whole living organism, it allows, for example, to evaluate the antiviral
activity in the organism as well as the effect on immune response, as well as the level of
toxicity of these compounds in different tissues.
For some products of natural origin, good results have been found in the study of their
antiviral and immunomodulatory properties in vivo. Table 7.4 summarizes some of these
studies.
TABLE 7.4 In-Vivo Studies Related to Antiviral Effects of Natural Products
Natural Products Virus/Animal Results References
Quercetin Rhinovirus/Mice Suppressed viral replication, decreased
expression of proinflammatory
cytokines, and improved lung function
Curcumin and rutin Human papillomavirus type
16/HPV16-transgenic mice
Resveratrol Rotavirus There was inhibition of viral replication
Cassia alata leaves
extract
Total flavonoid extracts
from Selaginella
moellendorffii hieron
Combination of
monoterpene alcohols
derived from Melaleuca
alternifolia
Ferulic acid, quercetin,
and glycyrrhizic acid
Dengue virus/mice Reduced viral titer in brain and
Coxsackie virus B3/mice Reduced mean viral titers in heart and
West Nile virus/mice Delayed morbidity and reduced viral
Influenza virus H5N1/mice Inhibited influenza virus H5N1 hemag-
Reduced tumor-associated
inflammation
and improvement of clinical profile
increased platelet count compared to
the control group
kidneys as well as mortality
titers in brain
glutinin-induced acute lung injury
⏎
Ganesan
et al. (2012)
Moutinho
et al. (2018)
Angelina
et al. (2022)
Yin et al.
(2014)
Pliego
Zamora
(2016)
Ke
(2022)
et al.
et al.
For many viral diseases, there is no ideal in-vivo study model. As an example of this, we
have dengue, since the dengue virus does not cause disease in other living beings besides
humans. What has been tried to do with dengue and with other viral diseases is to create
genetically modied in-vivo models, in such a way that viruses can infect them and/or
produce disease; however, the vast majority of these modications are generally carried
out in important immunological processes and the results obtained when using these study
models may not be as close to what could actually happen in humans or living beings not
genetically modied.
Despite the restrictions that exist when using some study models for evaluating the
effects of natural compounds, there is the great advantage that scientic and technological
advances allow us to carry out new research with better tools. A great advantage in this eld
is that for many of the compounds of natural origin for which antiviral properties have been
described, other effects have also been described, such as antiproliferative or anticancer
properties, and there are studies in these areas that already tell us about pharmacokinetics
and pharmacodynamics of some of these compounds in different models and even in humans