2021 Polyphenols and Their Potential .Pdf. 1

Science of the Total Environment 801 (2021) 149719
Contents lists available at ScienceDirect
Science of the Total Environment
journal homepage: www.elsevier.com/locate/scitotenv
Review
Polyphenols and their potential role to fight viral diseases: An overview

María Fernanda Montenegro-Landívar a,b, Paulina Tapia-Quirós a,b, Xanel Vecino a,b,c, Mònica Reig a,b,
César Valderrama a,b, Mercè Granados d, José Luis Cortina a,b,e,⁎, Javier Saurina d
a
Chemical Engineering Department, Escola d'Enginyeria de Barcelona Est (EEBE), Universitat Politècnica de Catalunya (UPC)-BarcelonaTECH, C/Eduard Maristany 10–14, Campus Diagonal-Besòs,
08930 Barcelona, Spain
b
Barcelona Research Center for Multiscale Science and Engineering, Campus Diagonal-Besòs, 08930 Barcelona, Spain
c
Chemical Engineering Department, School of Industrial Engineering-CINTECX, University of Vigo, Campus As Lagoas-Marcosende, 36310 Vigo, Spain
d
Department of Chemical Engineering and Analytical Chemistry, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain
e
CETAQUA, Carretera d'Esplugues, 75, 08940 Cornellà de Llobregat, Spain
H I G H L I G H T S G R A P H I C A L A B S T R A C T
• Fruits and vegetables residues are a nat-

ural source of polyphenols.
• Polyphenols, from agri-food industry,
present antiviral and antioxidant activi-
ties.
• Natural polyphenols could be used as a
treatment/prevention against virus in-
fection.
• Especially flavonoids are used for pre-
vention/cure of diseases caused by vi-
ruses.
• Polyphenols with antiviral activity could
be a novel strategy against SARS-CoV-2.
a r t i c l e i n f o a b s t r a c t
Article history: Fruits, vegetables, spices, and herbs are a potential source of phenolic acids and polyphenols. These compounds
Received 23 June 2021 are known as natural by-products or secondary metabolites of plants, which are present in the daily diet and pro-
Received in revised form 12 August 2021 vide important benefits to the human body such as antioxidant, anti-inflammatory, anticancer, anti-allergic, an-
Accepted 13 August 2021
tihypertensive and antiviral properties, among others. Plentiful evidence has been provided on the great
Available online 19 August 2021
potential of polyphenols against different viruses that cause widespread health problems. As a result, this review
Editor: Damià Barceló focuses on the potential antiviral properties of some polyphenols and their action mechanism against various
types of viruses such as coronaviruses, influenza, herpes simplex, dengue fever, and rotavirus, among others.
Also, it is important to highlight the relationship between antiviral and antioxidant activities that can contribute
Keywords: to the protection of cells and tissues of the human body. The wide variety of action mechanisms of antiviral
Agri-food residues agents, such as polyphenols, against viral infections could be applied as a treatment or prevention strategy; but
Phenolic compounds at the same time, antiviral polyphenols could be used to produce natural antiviral drugs. A recent example of
Antiviral activity an antiviral polyphenol application deals with the use of hesperidin extracted from Citrus sinensis. The action
Antioxidant properties
mechanism of hesperidin relies on its binding to the key entry or spike protein of SARS-CoV-2. Finally, the extrac-
Viral diseases
tion, purification and recovery of polyphenols with potential antiviral activity, which are essential for virus rep-
Polyphenol recovery
lication and infection without side-effects, have been critically reviewed.
© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
⁎ Corresponding author at: Universitat Politècnica de Catalunya (UPC)-BarcelonaTECH, C/Eduard Maristany 10-14, Campus Diagonal-Besòs, 08930 Barcelona, Spain.
E-mail address: jose.luis.cortina@upc.edu (J.L. Cortina).
https://doi.org/10.1016/j.scitotenv.2021.149719
0048-9697/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
M.F. Montenegro-Landívar, P. Tapia-Quirós, X. Vecino et al. Science of the Total Environment 801 (2021) 149719
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.1. Therapeutic tools against viral diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2. The potential of phenolic acids and polyphenols as antiviral agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1. Polyphenol recovery from secondary sources. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.2. Economic prospects of polyphenol recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.3. Stability, reactivity, synergism and bioavailability of polyphenols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.3.1. Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.3.2. Reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.3.3. Synergism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.3.4. Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3. Antiviral activity of polyphenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.1. Antiviral mechanism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.2. Relationship between antiviral activity and antioxidant properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Declaration of competing interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1. Introduction often damages or destroys infected cells, causing a viral disease

(Rouse and Sehrawat, 2010).
Since ancient times, plants have played an important role for hu- On this basis, it is necessary to find alternatives to the traditional
manity, for example as food, clothing, perfumes and/or medicines treatments for viral diseases (El-Toumy et al., 2018). For example, re-
(e.g., drugs in traditional medicine). Already in 1978, the World Health cently, the use of bioactive compounds like polyphenols has been pro-
Organization (WHO) highlighted the need of scientific research in tradi- posed as an alternative treatment due to their potential health
tional medicine. Since then it has begun to put in value this type of med- benefits. These substances can be found in vegetables and fruits and
icine, as well as to investigate the efficacy of the mechanism of action can also be recovered from secondary sources, such as agri-food resi-
and chemical bases of traditional herbal medicine for the development dues (Montenegro-Landívar et al., 2021; Tapia-Quirós et al., 2020). Sci-
of new drugs, and also within the antiviral property that some plants entific publications have detailed more than 500 different polyphenols
possess (Ruwali et al., 2013; World Health Organization, 1978). Addi- in more than 400 food components (Galanakis, 2018). Additionally,
tionally, it is known that plants produce secondary metabolites such based on epidemiological research and associated meta-analyses, the
as polyphenols to protect themselves from the plethora of biotic and long-term consumption of diets rich in polyphenols from plants are
abiotic stresses. Biotic stress can be weeds, insect pests, fungi, and considered as tools that could offer protection against for example to
other microorganisms, whereas abiotic stresses can be physical and en- cardiovascular diseases, neurodegenerative diseases, diabetes develop-
vironmental conditions like salinity, drought, UV radiation, extreme ment, osteoporosis, and cancers development among others (Pandey
temperatures, and toxic metals (Tuladhar et al., 2021). Polyphenols and Rizvi, 2009). Therefore, polyphenols are widely promoted to be
are not only involved in the defense mechanism of the plant system, used as functional foods or in drugs preparations accepted for human
but also, they have been found, for example, in the cell division, photo- consumption around the world (Cheynier, 2012; Shahidi and
synthetic activity, reproduction, hormonal regulation, and nutrient min- Ambigaipalan, 2015; Cory et al., 2018).
eralization mechanisms (Sharma et al., 2019). Thus, for instance, Recently, Russo et al. (2020), have proposed that alternative treat-
coumarins and tannins reduce stress on plants by repelling herbivores ments to antiviral drugs may also represent a valid approach for the
(Lattanzio, 2013). 2019-nCovid disease. It is also stressed that polyphenols, specifically fla-
Infections caused by viruses in humans are a critical and vitally im- vonoids, can act satisfactorily in various stages of the coronavirus entry
portant issue, as has been demonstrated during the last year with the and replication stages. Another example is catechin epigallocatechin-3-
2019-nCovid caused by SARS-CoV-2 (severe acute respiratory syn- gallate (EGCG), present in green tea leaves, which inhibits replication of
drome corona virus-2) (Gorbalenya et al., 2020), in particular to safe- DNA viruses such as herpes simplex (oral dose of 800 mg), and HIV-1
guard the health of the population and mitigate its impact on (concentration ranging from 25 to 250 μmol/L), among others
economic and social vectors. Therefore, antiviral agents (e.g., vaccines (Steinmann et al., 2013). Moreover, the half-maximal inhibitory con-
containing specific virus, or specific antibody with protective therapeu- centration (IC50) of 47–73 μM of luteolin, hesperetin, and quercetin,
tic effect, or plants with antiviral activity) are reported to fight viral dis- among others flavonoids, can inhibit key proteins (PLpro, 3CLpro) in-
eases, and some cases have been eradicated such as: i) smallpox, volved in the infectious cycle of SARS coronavirus (Nguyen et al.,
poliomyelitis (>99%); and ii) endemic measles, rubella and congenital 2012; Soukhova et al., 2004). More examples can be found as described
rubella syndrome practically eliminated from America since 2010 below, where a list of some types of viruses could be inhibited by phy-
thanks to vaccination (Plotkin et al., 2012). But although immunisation tochemicals such as polyphenols. Of the diseases caused by harmful vi-
and drug development have been progressing for decades, this has not ruses where the use of polyphenols has been critically reviewed and
been enough, as many viruses do not have preventive vaccines and, shown an antiviral activity against them, kaempferol and quercetin, ex-
worse still, traditional antiviral treatments such as drugs with unnatural tracted from Broussonetia papyrifera, have shown activity against MERS-
components (e.g., acyclovir for herpes) may lead to the generation of CoV and SARS-CoV-1 viruses; and hesperetin and naringenin block the
viral mutants (Lin et al., 2014). replication of Sindbis virus. Thus, these are examples which, with future
Besides, some drugs used to combat viral diseases can cause human developments, could be approved as alternative treatments. In view of
health hazards due to their viral resistance or, in some cases, low effi- above, the main objective of this comprehensive review is to compile
ciency. In addition, viruses are made up of DNA or RNA enclosed in pro- and evaluate the studies that have demonstrated the antiviral activity
tein capsules (Kamboj et al., 2012), which can invade human body cells of polyphenols, the postulated mechanisms of action of polyphenols to
and use components from those cells for their replication. This process defeat viruses as well as the synergy effect of antiviral and antioxidant
2
Table 1
Different families and type of viruses, their specific virus and the role of polyphenols as a possible alternative to treat virus.
Type of virus Specific virus Disease characteristics Conventional treatment Alternative treatment with Reference
polyphenols
Respiratory infections Influenza virus (A, B and C) Annually responsible for high mortality NA inhibitors and M2 protein channel
1,2,3,4,6-Penta-O-galloyl-ß-D-glucose (IC50 of (Fox and Christenson, 2014; Liu
in both humans and animals worldwide blockers after infection, while 2.36 μg/mL) purified from Echinacea et al., 2011; Moscona, 2008)
purpurea, Phyllanthus emblica Linn inhibits
vaccination is the most effective
therapy virus replication
Coronavirus (HCoV-229E, HCoV-OC43, Respiratory tract infections in humans Currently there are no specific Polyphenol extract from Echinacea purpurea (Chiow et al., 2016; Liu et al.,
HCoV-NL63, HCoV-HKU1, severe acute with outbreaks around the world, against SARS-CoV-2 provided 50% of
treatments for the CoV infection and 2020; Park et al., 2017; Signer
respiratory syndrome coronavirus especially in winter preventive vaccines are being inhibition et al., 2020)
(SARS-CoV), Middle East respiratory developed Kaempferol and quercetin from Broussonetia
syndrome coronavirus (MERS-CoV) and papyrifera against MERS-CoV and SARS-CoV
the novel SARS-CoV-2) effectively inhibited with an IC50 of 27.9 μM
and 30.2 μM, respectively
Rhinovirus The main cause of the common cold, There are no vaccines or antiviral Resveratrol showed a therapeutic approach (Choi et al., 2010;
M.F. Montenegro-Landívar, P. Tapia-Quirós, X. Vecino et al.
among other respiratory diseases, also agents for the prevention or treatment to reduce infection when the IC50 was 50 μM Mastromarino et al., 2015;
producing shortness of breath in of this virus Gallic acid, extracted (100 μg/mL) from Ruuskanen et al., 2013)
asthmatic people, acute otitis and Woodfordia fruticose flowers, reported 55%
bronchiolitis virus inhibition
Syncytial virus Causes infections in infants and the There is no safe and effective Resveratrol (IC50 189 pg/mL) inhibits 40% (Beigelman et al., 2014;
elderly, causing not only acute morbidity treatment. virus replication and down-regulates the Tagarro et al., 2014; Xie et al.,
but also recurrent breathing problems Corticosteroids was treated children of TIR-domain-containing adapter-inducing 2012)
preschool-age who had early interferon-β (TRIF) complex, which sends
bronchitis, but the results were not signals for the activation of innate immune
satisfactory and failed to reduce the cells
infection or breathing problems
Gastrointestinal infections Rotavirus Causes dehydrating gastroenteritis, There is a vaccine against rotavirus but Polyphenols (licocoumarone, glycyrin, (Crawford et al., 2017;
3
especially in children under five years of annually the mortality is around among others) extracted from Glycyrrhiza Cushnie and Lamb, 2005;
age 200,000 deaths worldwide. The uralensis root (EC50 18.7-69.5 μM) can inhibit Kwon et al., 2010)
treatment focuses on dehydration and 50% virus absorption and replication after the
not on the use of antiviral agents cell's entry
Hepatic infections Hepatitis virus (A, B and C) Cause high morbidity and mortality Anti-hepatitis virus drugs are Curcumin (150 μM) inhibits hepatitis B virus (Mouler Rechtman et al.,
around the world members of nucleotides or nucleoside 2010; Sukowati et al., 2016;
analogs, which inhibit the activity of Yugo et al., 2016)
polymerase or reverse transcriptase,
but the prolonged use giving rise to
the existence of mutant viruses
Epstein–Barr virus Infects human epithelial and lymphoid A vaccine is not yet approved (−)-Epigallocatechin gallate (EGCG) (Abba et al., 2015; Chang
cells. Infection is associated with a extracted from green tea (50 μM) blocked the et al., 2003; Cohen, 2018)
number of human cancers, such as EBV lytic cycle, inhibiting the transcription of
Hodgkin's disease immediate-early genes in a range of 40–50%
Human cytomegalovirus Not present obvious symptoms, but Drugs such as cidofovir, valganciclovir Curcumin, using a low dose of 0.2 μg/mL, (Ahmed, 2012; Evers et al.,
infection causes morbidity and mortality and ganciclovir, which target viral inhibits virus protein expression 2005; Lv et al., 2014)
in transplant recipients or patients with DNA polymerase, but their side-effects
acquired immunodeficiency syndrome include long-term toxicity, low
(AIDS) bioavailability, plus drug resistance to
the virus
Herpes simplex virus (HSV-1 and HSV-2) Responsible for orolabial and genital There is no vaccine and existing drugs Ent-epiafzelechin-(4 ∝ → 8)-epiafzelechin (Cheng et al., 2006; Morfin
diseases producing, in general, benign (e.g., acyclovir) do not eradicate the extracted from Cassia javanica leaves (250 μM and Thou, 2003; Piret and
lesions but, in some cases, putting the life virus infection and cause resistance to of) inhibits more than 90% of HSV-2 Boivin, 2011)
of patients at risk if the infections are drugs penetration to the host cell
recurrent
Exanthematous infections Varicella-zoster virus Causes fever and vesicular rash. Once the Generally, uses drugs such as acyclovir, Resveratrol (219 μM of) inhibits 100% virus (Docherty et al., 2006;
disease has disappeared, the virus enters valaciclovir, etc., which are often replication Johnson and Whitton, 2004)
into a state of latency, but it can be combined with analgesics for pain and
reactivated due to stress, causing herpes corticosteroids for inflammation
(continued on next page)

Table 1 (continued)
Type of virus Specific virus Disease characteristics Conventional treatment Alternative treatment with Reference
polyphenols
zoster and acute pain in latently infected

lymph nodes
Neurologic infections Rabies virus Causes an acute and fatal neurological Disease can be prevented by Tannin pentagalloylglucose (PGG) (10 μM) (Fisher et al., 2018; Riedel
infection in humans and mammals vaccination for 24 h possess significant anti-RABV et al., 2019; Tu et al., 2019)
activity; PGG can reverse the expression of
miR-455-5p (a microRNA whose excess
production regulates host cell signalling
pathways and innate immune responses)
Polio virus The virus drains into the cervical and The incidence has been largely Extract of Avicennia marina leaf, the IC50 was (Felipe et al., 2006;
mesenteric lymph nodes and then into reduced especially by the use of a 145.7 μg/mL before and 314.3 μg/mL after Racaniello, 2006; Zandi et al.,
the blood, causing a transient viremia vaccine, but the disease is still endemic attachment stages of virus replication, with a 2009)
in Africa and Asia cytopathic effect of 50% in both stages
Haemorrhagic fevers Dengue virus Causing from a mild fever to There are no effective vaccines, and Baicalein (IC50 was 7.14 μg/mL) potent (Zandi et al., 2011, 2012)
haemorrhagic fever, nausea, joint pains, the prevention options available for antiviral agent against adsorption in the host
M.F. Montenegro-Landívar, P. Tapia-Quirós, X. Vecino et al.
etc. the control of the virus infection are and after entry viral replication, and IC50 of
very limited 1.55 μg/mL presents a virucidal effect
Sindbis virus Cause of disease outbreaks in humans in There are no vaccines or therapeutic Hesperidin and naringenin with a 50% (Ling et al., 2019; Paredes
South Africa and Northern Europe means inhibitory dose (ID50) of 20.5 μg/mL and 14.9 et al., 2003)
μg/mL respectively, reaching 50% for
hesperidin and up to 80% for naringenin of
virus replication inhibition
Immune system infection Human immunodeficiency virus (HIV-1 Spreads through certain body fluids and Since HIV was discovered, there has Tricyclic coumarin compound from (Bhatti et al., 2016; Häggblom
and HIV-2) attacks the immune system, destroying T been no preventive vaccine for virus Calophyllum brasiliense stem bark (IC50 was et al., 2016; Kudo et al., 2013;
lymphocytes. Thus, the body loses its infection, and the applied treatment is 8.44 μM) inhibits virus replication by Lin et al., 2014; Sundquist and
ability to fight infections and diseases antiretroviral therapy drugs which suppressing nuclear factor-kappa B (a protein Kräusslich, 2012)
help control the multiplication of HIV complex that controls DNA transcription)
4
in infected patients activation
Multisystem diseases Coxsackie virus Causes muscle injury, paralysis and death There is no specific treatment or Apigenin ((EC50 of 9.7 mg/L) and ursolic acid (Bedard and Semler, 2004;
vaccine available (EC50 of6.6 mg/L) extracted from Ocimum Chiang et al., 2005; Wong
basilicum interfere with virus replication after et al., 2013)
infection
properties against viral diseases. Additionally, the extraction, purifica- Table 2

tion and recovery technologies to produce polyphenols from natural List of relevant polyphenol classified according to their structure (adapted from Saurina
and Sentellas, 2015).
products and/or agri-food waste are also evaluated, since they could
be limiting steps for the application of polyphenol molecules as an alter- Class Structure Substitutions Examples
native against viruses on a large scale. Phenolic acids R1: H, OH, Gallic acid
Hydroxybenzoic OCH3 Vanillic acid
1.1. Therapeutic tools against viral diseases acids R2: H, OH, Procyanidin B1
OCH3 Theogallin
Hydroxycinnamic R1: H, OH, Caffeic acid
The type of virus diseases and the specific virus considered in the re-
acids OCH3 Ferulic acid
view are summarized in Table 1, and includes: i) respiratory infections: R2: H, OH, p-Coumaric acid
influenza virus, coronavirus, rhinovirus, and syncytial virus; ii) gastroin- OCH3 Rosmarinic acid
testinal infections: rotavirus; iii) hepatic infections: hepatitis virus, Flavonoids R1: H, OH Hesperidin
Epstein-Barr virus, human cytomegalovirus, and herpes virus; iv) exan- Flavonols R2: H, OH Naringenin
thematous infections: varicella-zoster virus; v) neurologic infections: Flavones R3: H, OH Quercetin
rabies virus and poliovirus; vi) haemorrhagic fevers: dengue virus and Flavanones R4: H, OH Kaempferol
R5: OH, OCH3 Luteolin
Sindbis virus; vii) immune system infections: human immunodefi-
R6: H, OH
ciency virus; and viii) multisystem disease: coxsackie virus. Anthocyanidins R1: H, OH Cyanidin
In view of the examples described in Table 1, there are a large R2: OH, OCH3 Pelargonidin
number of viruses, which can affect human health to different extent. R3: OH
For this reason, it is important to identify new therapeutic and R4: H, OH
R5: OH
functional strategies using natural sources through bioactive com- R6: H, OH
pounds and, more specifically, polyphenols. Furthermore, it is worth Catechins R1-R3: OH Catechin
noting that polyphenols extracted from plants can efficiently inhibit R4: H, OH Epicatechin
the different stages of replication of various viruses in a dose- R5: OH Epigallocatechin
R6: H, OH
dependent matter.
Isoflavones R1: OH Genistein
2. The potential of phenolic acids and polyphenols as antiviral agents R2-R3: H, OH Daidzein
Plants not only have the function of feeding human beings, but have
Chalcones R1-R5: H, OH Xanthohumol
also been used since ancient times as a source of therapeutic agents. Ac-
Phloretin
cording to Naithani et al. (2008), up to 80% of the world population uses Isosalipurpurin
plants as alternative medicine for various reasons such as their well-
known antiviral features. This claimed activity is due to a wide variety
of bioactive compounds present, such as polyphenols, proteins, and ter-
penoids, among others (Kamboj et al., 2012). Although, polyphenols are Lignans R1-R2: H, OH Enterodiol
Matairesinol
common components of the human diet, it has been reported that poly-
phenols are also toxic due to their biocidal activity at intake concentra- Stilbenes R1-R4: H, OH, Resveratrol
tions between 1 and 5% of the total daily diet (Galanakis, 2018). OCH3 Piceatannol
Considering the significant amounts of compounds that a person must R5: H, OH
be consumed, being approximately between 0.025 and 1 g per day
(Scalbert and Williamson, 2000), and their multitude activities, it
should be noted that they could play an important role in the preven-
tion of numerous diseases, including antivirals. However, it is necessary
to consider that despite many promising results obtained in vitro or an- elements that bind these rings. Flavonoids are the largest and most
imal experiments, there is still not enough convincing evidence from studied group.
human studies, especially with large populations. More research is Phenolic acids possess a high antioxidant capacity and their medical
needed to better understand the value of therapeutic polyphenols, die- properties, such as vasodilatory, antibacterial, antiviral, anticarcinogenic
tary polyphenols, and in the context of their ability to prevent the pro- and anti-inflammatory, have been reported elsewhere (Oroian and
gression of diseases caused by viruses (Koch, 2019; Martin, 2009; Escriche, 2015).
Yang et al., 2020). An important derivation from hydroxybenzoic acids are the so-
The focus of this review is on phenolic compounds and polyphenols, called hydrolysable tannins, which are mostly present as phenolic poly-
which have a common structural feature consisting of the presence of mers with different molecular weights, from 500 to 3000 Da
one or more hydroxyl groups attached to a benzene ring. Polyphenols (Andronescu and Grumezescu, 2017). As their principal characteristic,
can be classified into different classes based on their chemical structure, tannins precipitate proteins, thus contributing to regenerate, for exam-
ranging from simple to highly polymerized compounds. Their funda- ple, a burn tissue, besides their antimicrobial, antioxidant and antiviral
mental physiological functions deal with the growth and reproduction properties (Haminiuk et al., 2012). Their antiviral activity against
of plants, as well as protection against pathogenic organisms and ultra- Epstein–Barr virus DNA polymerase has been demonstrated, and espe-
violet radiation. In addition, polyphenols strongly influence the organo- cially those tannins extracted from mouse-tail plant (Phyllanthus
leptic characteristics of food products, such as color and flavour (Ignat myrtifolius) and chamber bitter (Phyllanthus urinaria) (Naithani et al.,
et al., 2011). 2008).
Polyphenols are often classified into four main families, namely: Regarding flavonoids, they represent the largest amount of polyphe-
phenolic acids, flavonoids, stilbenes and lignans (Saurina and nols (up to 60%) consumed in the human diet (Brglez Mojzer et al.,
Sentellas, 2015). The basic chemical structure and examples of these 2016). Actually, more than 9000 different flavonoids have been re-
polyphenol families are collected in Table 2. ported, having important benefits on human health because of their an-
As shown in Table 2, polyphenols have a great structural diversity as tiviral, anti-inflammatory and antidiabetic attributes (Zhang et al.,
a function of the number of phenol rings that they contain and the 2015; Krych and Gebicka, 2013; Tian et al., 2013; Ragab et al., 2014).
5
Table 3
Summary of relevant polyphenols present in plants with antiviral activity according to the reviewed publications.
Plant source Polyphenol Type of virus Reference
Berries, tea, almond, beans, tomato, Ficus carica Kaempferol Coronavirus, rotavirus, human cytomegalovirus, HSV-1 (Naithani et al., 2008; Kamboj et al., 2012; Russo et al.,
L., capers, caraway, cloves, cumin, Cambuci and HSV-2, coxsackie B virus 2020; Watson et al., 2013; Haminiuk et al., 2012)
Propolis, Oroxylum indicum Chrysin Coronavirus, rotavirus, human cytomegalovirus, HSV-1 (Cheng and Wong, 1996; Kumar and Pandey, 2013;
and HSV-2, coxsackie B virus Cushnie and Lamb, 2005)
Euphorbia cooperi, Morus alba, Rhus succedanea Catechin HIV, HSV-1 (Kamboj et al., 2012; Cushnie and Lamb, 2005;
El-Toumy et al., 2018)
Citrus spp., cocoa, fish mint (H. cordata), Quercetin Rabies virus, poliovirus, syncytial virus, HSV-2, (Suárez et al., 2010; Silva et al., 2011; Zandi et al.,
Spondias mombin, Spondias tuberosa respiratory syncytial virus, dengue virus, coronavirus 2011; El-Toumy et al., 2018; Chiow et al., 2016)
Betula pendula, apple Quercitrin Rabies virus, HSV-1, influenza virus (Kumar and Pandey, 2013; Suárez et al., 2010)
Spondias spp., Pavetta owariensis (bark) Rutin Rabies virus, influenza virus, dengue virus (Kamboj et al., 2012; Cushnie and Lamb, 2005)
Citrus spp., peppermint, grapefruit Hesperidin Influenza virus, HSV, poliovirus, syncytial virus, (Mhatre et al., 2020; Bellavite and Donzelli, 2020)
SARS-CoV-2
Chamomile, parsley, oregano, thyme, grapefruit, Apigenin HSV-1, HIV (Kumar and Pandey, 2013; Kamboj et al., 2012)
orange, onion, mango
Citrus spp., tomato, aromatic plants Naringin Respiratory syncytial virus (Kumar and Pandey, 2013)
Broadleaf plantain (Plantago major), papaya, Caffeic acid HIV, HSV (Pommier et al., 2005; Sytar et al., 2021)
peach, avocado
Broccoli, rosemary, pistachio, lentils, olive, Luteolin HSV-1 and HSV-2 (Naithani et al., 2008; Lopez-Lazaro, 2008)
artichoke, lemon, Aloe vera
Berries, pomegranate, walnuts, pecans Ellagic acid Dengue virus, hepatitis A and B (Kang et al., 2006; Kamboj et al., 2012)
Grape, berries, peanuts Resveratrol Influenza A, hepatitis C virus, respiratory syncytial virus, (Docherty et al., 2006; Mastromarino et al., 2015)
varicella-zoster virus, Epstein–Barr virus, HSV, HIV
Flavonoids have been studied against the type-1 and type-2 herpes sim- organic and/or aqueous solvents. For their subsequent purification im-
plex virus, and against the human immunodeficiency virus (HIV-1 and plies a preliminary stage of clean-up and concentration by using sorp-
HIV-2) (Naithani et al., 2008). tion on resins, or pressure-driven membrane processes such as
Finally, stilbenes (including curcuminoids) and lignans have been microfiltration (MF), ultrafiltration (UF), nanofiltration (NF) and re-
extensively studied because of their antioxidant properties, but their verse osmosis (RO) followed by a final purification by using extraction
antiviral activity is not far behind. These compounds and their derivates chromatography (Bottino et al., 2020; Charcosset, 2016).
have been studied against viruses such as herpes simplex (type-1 and As mentioned, the commonest technique for polyphenols extraction
type-2), HIV, influenza, and human papilloma, among others is maceration (e.g., a solid-liquid process). For example, Edziri et al.
(Naithani et al., 2008; Abba et al., 2015). (2012) used maceration for polyphenol extraction from Marrubium
A list of polyphenols with antiviral activity, the type of virus against deserti. The dried product (250 g) was extracted with methanol, buta-
which they act, and their plant source is collected in Table 3. nol, chloroform and ethyl acetate (using a feed to solvent ratio of
As shown in Table 3, polyphenols with antiviral activity such as 1:10) for an extraction time of five days. Results from antiviral activity
quercetin, rutin, hesperidin, apigenin, catechin, and morin are present tests concluded that the extracts with methanol and ethyl acetate
in abundance in plants like fruits (e.g., berries, citrus fruits, tropical showed significant antiviral activity against coxsackie B3 virus with
fruits), popular beverages (e.g., green tea, coffee), vegetables IC50 of 100 and 135 μg/mL, respectively.
(e.g., spinach, beans, onions, olives), spices and herbs (e.g., turmeric, Magnetic agitation at 20 °C has been applied to recover active com-
rosemary, ginger), which are consumed in the daily human diet ponents from apple pomace (10 g) using 100 mL of 70% acetone and
(Brglez Mojzer et al., 2016). Currently, the antiviral activity of various 80% methanol in darkness. The results showed that acetonic and meth-
polyphenols makes their study more attractive; for example, 3 mg/kg anolic extracts could inhibit the replication of HSV-1 and HSV-2 by more
body weight of curcumin, extracted and purified from turmeric, is suffi- than 50% (Suárez et al., 2010).
cient to inhibit HIV (Praditya et al., 2019; Barthelemy et al., 1998; The purification of plant extracts is, in general, a complex pro-
Haslberger et al., 2020). cess and no single method is complete enough. It requires a combi-
nation and integration of them to achieve the highest separation
2.1. Polyphenol recovery from secondary sources and purification factors. A successful example is the study by
Zahoor et al. (2020), who compared the separation efficiency of
Phenolic compounds can also be obtained from by-products of plant quercetin extracted from Rubus fruticosus by using RO and NF
processing, being cheap and easily available to recover them following a membranes. Quercetin is used against rabies virus, poliovirus, syn-
circular economy strategy (Tapia-Quirós et al., 2020; Montenegro- cytial virus, and HSV-2, among other viruses (Suárez et al., 2010;
Landívar et al., 2021). In addition, the growing interest in polyphenols Silva et al., 2011; Zandi et al., 2011; El-Toumy et al., 2018; Chiow
recovery has led to the study of different technologies that can allow et al., 2016). The results obtained indicated that the RO membrane
their extraction without losing their antiviral properties (Dzah et al., accomplished a quantitative recovery (e.g., >99%) of the drainage
2020). Successful cases of extraction and recovery of polyphenols with pipe, while NF membranes achieved a 95% of polyphenol recovery.
antiviral activity is summarized in Table 4. The study shown that the cost of use the RO membranes is higher,
Table 4 lists not only the application of polyphenols extracted from due to the higher energy consumption than the use of NF mem-
different plant sources against numerous target viruses, but also the dif- brane stage followed by a sorption stage of the remaining 5% of
ferent extraction techniques integrated, being maceration the most the permeate stream by using magnetic carbon nanocomposite.
used. Additionally, most of the trials were carried out on a pilot scale. It should be noted that the phenolic compounds recovered from ex-
The polyphenols extraction from plants or from their processing tracts, such as kaempferol, luteolin, chrysin, gallic acid, ferulic acid, cat-
wastes can be achieved by conventional (e.g., mechanical stirring) and echin, anthocyanins among others, could be used as a treatment and/or
enhanced (e.g., ultrasound and microwave assisted) solid-liquid extrac- prevention against virus infection (Singh et al., 2020; Kumar and Goel,
tions or by combination of both extraction approaches by means of 2019; Watson et al., 2013; Marín et al., 2015).
6
Table 4
Applications of extracted polyphenols from different plant sources to treat several target viruses.
Antiviral polyphenol Plant source Target Extraction Purification Study effectiveness Results Scaling-up Reference
virus technique technique against virus
1,2,3,4,6-Penta-O-galloyl-ß- Pomegranate Influenza Maceration Sephadex EC50 2.36 ± 0.29 Significant inhibition virus Lab scale (Liu et al., 2011)
D-glucose (PGG) A (H1N1) LH-20 μg/mL of PGG 5 or 8 h release
column upon infection
Extract rich in polyphenols Magnolia Influenza PLE – In vivo oral Infected mice reduce the Pilot scale (Wu et al., 2011)
officinalis A (H1N1) administration (10 andproduction of nitric oxide,
bark 20 mg/kg) for 5 days pro-inflammatory cytokines,
TNF-α and IL-6
Isoquercetin (quercetin Hypericum Influenza Maceration – In vivo administrated Reduce virus titres and Pilot scale (Kim et al., 2010)
glucoside form) perforatum, A (H1N1) intraperitoneal pathological changes in lungs
Equisetum of mice infected with influenza
arvense L. A (H1N1) by up to 20-fold at
1:500 (Equisetum arvense L.) or
1:1000 dilutions (Hypericum
perforatum) at 24 h
post-inoculation
Baicalein Scutellaria Influenza Maceration – In vivo oral Infected mice showed Pilot scale (Xu et al., 2010)
baicalensis H1N1 administration significant therapeutic
root activities, including death
prevention and lung virus
titre reduction
Quercetin, kaempferol, Geranium Influenza Maceration – Administered in Around 70% was the Pilot scale (Serkedjieva et al.,
myricetin, sanguineum (H3N2) aerosol way (dose 5.4 protective index and the 2008)
quercetin-3-O-galactoside, aerial roots mg/mL) survival time was in a range
morin, apigenin, catechin, of 2.9–4.9 days, the animal
epicatechin, caffeic acid lung infectious virus titre was
and rimantadine reduced in comparison with
control
Epigallocatechingallate Tea Influenza Maceration – 76 adult persons The catechin-treated group Pilot scale (Yamada et al., 2006)
(EGCG), epigallocatechin around 65 years old have lower incidence of
(EGC), epicatechingallate gargling 200 mg/mL influenza infection than the
(ECG), epicatechin (EC) 3 times daily for 3 control group
and catechin gallate months
2.2. Economic prospects of polyphenol recovery However, the extraction yields of the three techniques were similar
(PLE 11 ± 1, Soxhlet 12 ± 1 and LPSE 12 ± 1).
Taking into account the different antiviral applications of polyphenol On the other hand, Ioannou-Ttofa et al. (2017) determined that the
extracts, as well as the need to investigate innovative extraction and pu- total cost of the treatment of olive mill waste water through an inte-
rification procedures, it is interesting to mention some examples of the grated process using UF and NF membranes (UFZW-10/NF270) was
economic evaluation of the recovery of polyphenols, which is also appli- 9.94 €/m3. The high-added value polyphenols present in this stream,
cable to antiviral polyphenols. like hydroxytyrosol, can be purified, and the cost can reach 14,900 to
The manufacturing cost (COM), expressed as €/kg per year, of the 20,900 €/kg.
polyphenols extraction from raw material could be estimated using Besides, it is worth noting that the approximately market value, ac-
the methodology described by Turton et al. (2009), where five main cording to the Sigma-Aldrich website, of 10 mg of kaempferol (≥90% pu-
costs must be taken into account: (i) fixed capital investment (FCI), rity) is 113 €, 10 mg of luteolin (≥98%) is 169 €, 10 mg of apigenin
(ii) cost of operating labour (COL), (iii) cost of utilities (CUT), (iv) cost (≥97%) is 92 €, 10 g of quercetin (≥95%) is 44 €, 10 g of rutin (≥94%) is
of waste treatment (CWT), and (v) cost of raw material (CRM). Follow- 24 € and 10 mg of hydroxytyrosol is 191 € (≥90%), but their purity can
ing this methodology, Vieira et al. (2013, 2017) compared the COM of make they more expensive.
extraction of jussara pulp (Euterpe edulis Martius) with strong antioxi-
dant activity by ultrasonic assited extraction (UAE) and agitated bed ex- 2.3. Stability, reactivity, synergism and bioavailability of polyphenols
traction (ABE) at lab scale. The UAE extracts presented a higher cost
(75.2–137.2 €/kg) than the ABE extracts (72.5–139 €/kg). It was re- Technically, polyphenols are extracted, purified and concentrated
ported that the ABE and UAE extracts contained polyphenols such as from plants using different techniques as described above, which can
kaempferol, luteolin, apigenin, quercetin and rutin, which may have be processed into tablets or capsules for human consumption. However,
medical applications (e.g., antivirals) for human health; and polyphenols are unstable, prone to degrade and/or react with some ele-
anthocyanidins as natural pigments for feed applications (Favaro et al., ments (e.g., oxygen and metal ions during their processing and storage
2018; Vieira et al., 2017). Moreover, Osorio-Tobón et al. (2014) also stages), resulting in changing structures and decreasing activities
used the COM methodology to evaluate the extraction process of (e.g., antiviral activity) (Galanakis, 2018). Therefore, the stability as
curcumin from turmeric (Curcuma longa Linneo), which possesses a re- well as their reactivity, synergism and bioavailability of polyphenols
markable antiviral effect against dengue virus (Ichsyani et al., 2017). are the main aspects that must be taken into account in the recovery,
When advanced solid-liquid extractions techniques were evaluated, processing, storage and consumption of phenolic compounds for their
pressurized liquid extraction (PLE), Soxhlet extraction and low- market applications.
pressure solvent extraction (LPSE), COM values of 79, 204 and 161 €/
kg, respectively were estimated. The results showed that the PLE extrac- 2.3.1. Stability
tion technique was less expensive due to the short extraction time re- Instability generally due to many polyphenols are sensitive to chem-
quired (e.g., 30 min) compared with 6 h for Soxhlet and 3 h for LPSE. ical, enzymatic and physical treatments, which are used in food
7
processing. Chemical and enzymatic instability leads to changes such as 3. Antiviral activity of polyphenols
oxidation or polymerization, among others, causing alterations on their
nutritional and physical-chemical attributes. Physical instability leads to The antiviral activity of different polyphenols has the target of
changes like phase separation, flocculation, etc. that can also alter their interacting directly with viral particles, but this binding will depend
attributes (Joye and McClements, 2014; Zhang et al., 2020). on the nature of the virus (DNA or RNA virus) (Sundararajan et al.,
2010; Palamara et al., 2005; Liu et al., 2011). Another characteristic of
2.3.2. Reactivity antiviral polyphenols is that they can exert the activity during intracel-
Another factor that influences polyphenols is their reactivity, as they lular replication, which may be attributed to antioxidant features of
can be enzymatically degraded and polymerized during food processing phenolic groups, thus inhibiting the oxidation of cells by the replication
stages. One of the most notable enzymatic reactions is on color, taste of some viruses (Sundararajan et al., 2010; Fraternale et al., 2009).
and nutritional value of polyphenols, which can even cause significant Many natural polyphenols have provided research results and are
economic problems due to their impact on quality and shelf life of the becoming an important target in the development of some drugs to
products (Galanakis, 2018). combat viruses, thanks to their wide availability, inexpensive produc-
tion and, above all, their low side-effects (Kumar and Goel, 2019; El-
Toumy et al., 2018). This is the case with the virus that is currently
2.3.3. Synergism attacking the entire world, the novel severe acute respiratory syndrome
The synergism of polyphenols in plant extracts means that a combi- coronavirus type 2 (SARS-CoV-2), which causes the 2019-nCoV disease
nation of two or more of compounds creates a higher biological activity transmitted person-to-person (Kampf et al., 2020).
than when the extracts are analyzed relative to individual polyphenols As of June 2021, a total of nearly 171 million confirmed cases have
isolated from the same extracts (Yao et al., 2012; Zhang et al., 2020). been reported, including almost 4 million deaths worldwide since the
However, the commercial application of polyphenols is currently lim- start of the outbreak (World Health Organization, 2020). Due to the
ited due to instability when exposed to light, heat or oxygen as well as high infectivity and mortality rate of SARS-CoV-2, there is an opportu-
low bioavailability. A solution of the limitations mentioned, it could be nity to use the great amount of information on plants used in the Tradi-
the encapsulation (Zhang et al., 2020). Long et al. (2015) showed that tional Chinese Medicine (TCM) to be used to treat symptoms related to
bioactive food compounds can produce synergistic effects, as they SARS (homology of SARS-CoV and SARS-CoV-2), considering that natu-
have been reported in traditional Chinese medicine research. Therefore, ral polyphenols could inhibit SARS-CoV-2 (Mehany et al., 2021). Ac-
the synergism between polyphenols must be taken into account for the cording to Wang et al. (2020) and Chojnacka et al. (2020), the entry of
development of functional foods and thus promote human well-being SARS-CoV-2 into the host cells (lung epithelium) is facilitated by a tri-
and prevent diseases such as viral ones. meric glycoprotein, called the spike protein (protein S), located in the
capsid of the virus (outer envelope). SARS-CoV-2 uses angiotensin
2.3.4. Bioavailability converting protein II (ACE2) as a receptor for binding to host cells. The
Bioavailability plays an important role in terms of the biological protein S is hydrolysed by endosomal proteases, such as cathepsin or
properties of polyphenols, which makes it possible to understand the transmembrane cellular serine protease 2 (TMPRSS2), which results in
proportion of their absorption, digestion and metabolism after their membrane fusion. After the virus enters the host cell, it produces new
entry into the circulatory system (Carbonell-Capella et al., 2014). Sev- RNA and the proteins that form its envelope. The binding of SARS-
eral epidemiological and experimental studies describe the protective CoV-2 to the receptor ACE2 may depend on several factors, such as var-
role of polyphenols in diseases such as viral diseases, diabetes, inflam- iants in the virus protein S that promote the efficiency of their interac-
mation, among others (Kumar and Goel, 2019). Scalbert and tion. In the replication and transcription, the main protease 3CLpro and
Williamson (2000) reported few human bioavailability studies showing papain-like protease (PLpro) are involved. The therapeutic targets to
that the amounts of intact polyphenols in urine vary from one to an- protect the human body from the entry, replication and transcription
other polyphenols. For example, for quercetin glycoside the percentage of the SARS-CoV-2 virus are the receptor with the proteases cutting
found in excretion urine was between 0.3 and 1.4%, while in the case of spike protein and the proteases. Polyphenols with antiviral activity
hesperidin, it was 24.4%. Similar variations were also observed for (e.g., flavonoids such as kaempferol, quercetin, and naringenin, see
naringin consumed with grapefruit juice depending on the individual Table 3) have been developed as protease inhibitors, helping to stop
(5 to 57%). virus infection (e.g., HIV, MERS and SARS) (Paraiso et al., 2020). Current
Hong et al. (2014) and Liang et al. (2017) demonstrated that EGCG studies show that some extracted polyphenols have antiviral activity,
loading in nanoparticles constructed with zein a protein as zein or specifically as protease inhibitors. Park et al. (2016) used 95% ethanol
with a polysaccharide as chitosan, improved the stability of said poly- to extract chalcones from Angelica keiskei that showed inhibition of pro-
phenols at the gastrointestinal level. Another study by Xue et al. tease 3CLpro as well as non-competitive inhibition of protease PLpro of
(2014) using glycosylated casein nanoparticles to encapsulate EGC SARS-CoV with IC50 values of 11.4 and 1.2 μM, respectively. Also Park
demonstrated the improvement of its physical stability during storage. et al. (2017) extracted polyphenols with ethanol from Broussonetia
Xue et al. (2018) encapsulated curcumin in zein-caseinate nanoparti- papyrifera with potential anti-coronaviral agents, which inhibit 100%
cles, and reported improved stability against UV radiation and heat PLpro (the IC50 was 3.7 μM) protease. Recent studies, such as Yudi
treatments. Utomo and Meiyanto (2020), reported that hesperidin and naringenin,
On the other hand, there has also been an interest in encapsulating among other citrus flavonoids, and polyphenols from Curcuma spp.,
combinations of polyphenols and taking advantage of their synergistic such as curcumin, bind strongly to the 3CLpro substrate, the binding
effects. For example, curcumin and resveratrol have been encapsulated domain of SARS-CoV-2, while interacting with the receptor ACE2 and
within hyaluronic-coated lipid droplets, as they have similar mecha- protein S. Khalifa et al. (2020a) demonstrated that anthocyanidins,
nisms of action to inhibit tumor cell growth and antioxidant and antivi- such as cyanodelphine, phacelianin, techofilin and gentiodelphin, au-
ral effects (Nasr, 2016). Encapsulated polyphenols have been shown to thentically interact with the receptor binding site of SARS-CoV-2-
have better chemical stability that non-encapsulated ones. However, 3CLpro. Khalifa et al. (2020b) found that pedunculagin, castalin and
after encapsulation no improvement in the bioavailability of polyphe- tercatain, which are tannins, strongly interact with the SARS-CoV-2-
nols has been observed, as polyphenols can become indigestible. There- 3CLpro receptor binding site. Other polyphenols such as sinigrin, with
fore, the most appropriate administration system for the polyphenols IC50 of 217 μM, and hesperidin, with IC50 of 8.3 μM, contained in the
and the food matrix used should be thoroughly evaluated case by case water extract of the root of Isatis indigotica, have also been shown to
(Dueik and Bouchon, 2016). be anti-SARS-CoV-2-3CLpro (Xu et al., 2020). These studies triggered
8
Table 5
Selected polyphenols and their role against SARS-CoV-2.
Polyphenol Source Mechanism of action Analysis Reference

study
Kaempferol, quercetin, luteolin-7-glucoside, Medicinal plants Block the enzymatic activity of In silico (Khaerunnisa et al., 2020)
demethoxycurcumin, naringenin, SARS-CoV-3CLpro
apigenin-7-glucoside, oleuropein, curcumin,
catechin, epicatechingallate, zingerol, gingerol,
and allicin
Malvidin, peonidin, petunidin, pelargonidin, Pimpinella anisum L. Binding affinities to 3C-like protease of In silico (Hasan et al., 2020)
cyanidin and malvidin SARS-CoV-2 (virus replication)
Hesperetin, myricetin, caflanone, linebacker Medicinal plants High affinity to protein S, helicase and In silico and in vitro (Ngwa et al., 2020)
protease sites on the CE2 receptor (in silico
analysis); in vitro analysis shows potential
caflanone to inhibit virus entry
Baicalein and baicalin Scutellaria baicalensis Down-regulators of the TMPRSS-2 expression. In silico and in vitro (Da Silva Antonio et al., 2020)
and Oroxylum Baicalein (IC50 of 0.94 μM) and baicalin (6.41
indicum μM) promising results to 3Clpro
Polyphenol extract Echinacea purpurea Virus inactivated upon treatment with 50 μg/mL In vitro (Signer et al., 2020)
that some polyphenols could be used as effective and above all natural (Isatis indigotica), Bunge Corydalis (Corydalis bungeana), Mongolian
anti-2019-nCovid components. Even, the Chinese Health Commission Dandelion (Taraxacum mongolicum), Scutellaria Amoena (Scutellaria
officially confirmed that natural medicine (e.g., TCM) should be used baicalensis) as well as more than 180 compounds (e.g., polyphenols
in combination with conventional medicine for the treatment of 2019-
nCovid patients, and currently experimental research is focused on the
therapeutic potential of polyphenols against SARS-CoV-2 (Yang et al.,
2020). Table 5 collects a summary of the antiviral activities of recent
studies of natural polyphenols and their mechanism of action against
SARS-CoV-2.
Although Table 5 present more in silico experiments that predict
Proanthocyanin
promising results, more in vitro and in vivo studies are needed to eval- Virus adsorption
uate the mechanism of action of polyphenols against SARS-CoV-2. Most
of the studies were carried out in silico, current technology to predict
drug behavior, accelerating the detection rate, since it allows screening
many drugs and reduction of the cost of laboratory work, limiting clin-
ical trials to the best candidates.
Recently has been discovered that hesperidin (which is a flavonoid)
easily binds to key proteins of the SARS-CoV-2, due to its physicochemical Virus-cell fusion
structure (see Table 2) (Adem et al., 2020; Chen et al., 2020; Das et al.,
2021; Joshi et al., 2020; Wu et al., 2020; Yudi Utomo and Meiyanto,
2020). These authors investigated if hesperidin is able to bind with a
low binding energy. The lower energy required, the stronger and more
specific the binding will be in therapeutic terms. Wu et al. (2020) tested
hesperidin as a potent antiviral agent. The binding of hesperidin to the
Uncoating
spike protein was effective in superimposing the ACE2-receptor binding
domain (RBD) on the hesperidin-RBD complex, where a clear overlap of
hesperidin with the ACE2 interface was observed. Accordingly, it was con-
Reverse transcription Epigallocatechin
cluded that hesperidin can interrupt the ACE2 with RBD. Another low-
energy binding site for hesperidin against SARS-CoV-2 is the main prote-
ase. This enzyme is called 3CLpro or Mpro and is the target of many chem- Integration
ical antiviral drugs. Das et al. (2021) studied the molecular coupling of the
interaction between hesperidin and Mpro. The binding energy of hesperi-
Chrysin Transcription
din with hydrogen bonds to various amino acids (e.g., THR24, THR45,
HIS4, SER46, etc.) was estimated as −37.7 kJ/mol. Finally Joshi et al.
(2020) identified that hesperidin binds strongly to the main SARS-CoV- Quercetin
Translation Rutin
2 protease, and also to the ACE2-receptor. Quercetin
Morin
Regarding vitro analysis, Suru et al. (2021) confirmed that pome- Catechin
granate peel extract and its main polyphenols, such as punicalin and Proteolytic processing
punicalagin, have a great capacity to attenuate the binding of the by viral protease
SARS-CoV-2 glycoprotein S to the ACE2 receptor. The most pronounced Viral proteins and RNA
in vitro activity was observed in pomegranate peel extract, suggesting a assemble at the cell membrane
possible synergistic effect of polyphenols, allowing their possible thera- Budding
peutic application for 2019-nCovid.
On the other hand, there are few in vivo studies investigating the an-
tiviral effect of polyphenols against this novel virus. Deng et al. (2020),
studied Pudilan Xiaoyan Oral Liquid (EC50 of 1.078 mg/mL), a Fig. 1. Virus replication and polyphenol targets (adapted from Pommier et al., 2005;
traditional Chinese medicine containing four herbs: Indigowoad root Kamboj et al., 2012).
9
Table 6
Examples of antiviral mechanism of polyphenols (adapted from Naithani et al., 2008; Haslberger et al., 2020).
Antiviral polyphenol Plant source Study Virus type Main mechanism
4′,5-Dihydroxy Agastache rugosa Effect on the replication Rhinovirus coxsackie virus Replication inhibition, selective inhibition of viral RNA
3,3′,7-trimethoxy flavone (Kuntze) virus synthesis in the cell culture
Quercetin Luteolin Achyrocline satureioides Effect on the viral HSV-1 Interferes with the events occurring between the third and
replication cycle of HSV-1 ninth hour of HSV-1 replication cycle, which includes
transcription and translation of viral proteins
Salvin Salvia officinalis Viral inhibitory before HSV-1, HIV, SARS-CoV Efficacy before absorption stage, but not in the replication stage
absorption stage
Morin Rhus succedanea, Effect on viral replication HIV Blockage of RNA synthesis, exhibited HIV-inhibitory activity
Coumarin Garcinia multiflora,
Quercetin Alnus firma
such as chrysin, apigenin, rutin among others), which exhibited po- Experimental animal models have achieved high levels of reactive oxy-
tent anti-SARS-CoV-2 activity in infected hACE2 mice. In another gen species (ROS) and an alteration of innate antioxidant defenses dur-
study, Schettig et al. (2020) reported that a nebulized formulation ing, for example, a SARS-CoV infection (van den Brand et al., 2014).
of quercetin (20 mg/mL) and N-acetylcysteine (100 mg/mL) greatly Therefore, the use of polyphenols with antiviral and antioxidant ac-
alleviated the respiratory symptoms of SARS-CoV-2 in a patient tivities could be an alternative to prevent the onset of infection or devel-
treated with hydroxychloroquine and antibiotics. This demonstrates opment of viral disease. For example, Lin et al. (2002) reported that
the importance of conducting further clinical (in vivo) studies to HSV-2 infection increases the amount of free radicals, and consequently
evaluate the potential of polyphenols as an adjuvant or primary ther- causes immune response pathology. They used an ethyl acetate extract
apy for 2019-nCovid. from Euphorbia thymifolia with antiviral and antioxidant activities (the
If polyphenols are analyzed in depth as traditional anti-2019-nCovid IC50 was 7.72 ± 0.15 μg/mL) to inhibit HSV-2 growth in the kidney
therapeutics on humans, they could be innovative and effective, or even cell line.
against other lethal viral diseases. The use of medicinal plants contain- As mentioned, many of the pathological effects of the viruses are not
ing antiviral polyphenols, still has some risks and needs massive and ad- only directly related to viral replication, but also to the host response to
ditional experiments. infection (e.g., inflammation, oxidative stress, etc.) (Mateos-Martín
et al., 2014; Bellavite and Donzelli, 2020). Therefore, the combination
3.1. Antiviral mechanism of antiviral therapy with the antioxidant properties could help
favourably to combat the virus infection, reducing toxicity and
The mechanism of polyphenols deals with the prevention of the preventing antiviral resistance.
entry of the virus into the host cell. This was the case of the
proanthocyanidins extracted from Rumex acetosa, which inhibited the 4. Conclusions
entry of the influenza type A virus in its first critical phase (Daglia,
2012). Fig. 1 shows the scheme of the target sites of the antiviral mech- Keeping in mind that diseases caused by viruses remain among the
anism of some polyphenols (e.g., quercetin, morin, chrysin). leading causes of morbidity and mortality, in both developed and devel-
The general interest in polyphenols, as antiviral agents, is increas- oping countries, despite having conventional medicine, it is of interest
ing because of the great advantages of using nature-derived com- to looking for alternative treatments more biocompatible for humans.
pounds with almost no side-effects on human health (Naithani As an example of alternative treatments, polyphenols are interesting
et al., 2008). Several studies have been done for discovering the an- and promising molecules that could be applied in the pharmaceutical
tiviral mechanism of different polyphenols; Table 6 gives an over- sector. Polyphenols are secondary metabolites from plants which can
view of some of them. also be extracted from agri-food residues. The bioactivities of polyphe-
As shown in Table 6, the polyphenols with antiviral properties may nols, like antioxidant capacity, as well as their mechanisms, such as
have different mechanisms of action, such as inhibiting the entry of forming stable radicals, delay and/or prevent oxidative stress-induced
the virus, an effect on replication, etc. (Haslberger et al., 2020). New cellular damage and disease, are well defined and studied. However,
trends in biotechnology and medicine, as well as new processing tech- in this comprehensive review, it has specifically shown the potential
nologies, could help to optimise the solubility, administration and ther- role of polyphenols with potential targets, such as antiviral activity, in
apeutic activities to prevent infection by viruses (Patra et al., 2018; the prevention of diseases caused by viruses. The state of the art indi-
Thomford et al., 2018; Lin et al., 2014). cates that there is not a single mechanism of action of polyphenols
against viruses. Indeed, the antiviral mechanism of these bioactive com-
3.2. Relationship between antiviral activity and antioxidant properties pounds could be by antioxidant activities, viral entry or inhibition of
viral reproduction, DNA inhibition among others.
The study of the relationship between antiviral and antioxidant Additionally, due to the complex polyphenol structure, new extrac-
activities has not been explored in depth. Only a few studies report tion, purification, formulation and processing technologies could help
a comparative evaluation. It is worth mentioning that a high forma- to improve the stability and bioavailability of antiviral polyphenols, as
tion of free radicals leads to an imbalance in the oxidative metabo- well as the administration protocols and the therapeutic effects as anti-
lism at the mitochondrial level and, as a result, the vitality of the viral treatments. Thus, the use of plant extracts, as polyphenols, is pos-
cells of each tissue is affected (Delgado-Roche and Mesta, 2020). tulated as useful for health, due to their synergistic effects, such as
This imbalance can be caused by various viruses (e.g., SARS-CoV-2, antioxidant, antiviral, anti-inflammatory, among others that must be
HIV, influenza virus) and leads to oxidative stress and helps the considered and studied intensively. Therefore, future and more compre-
virus life cycle and eventually causes cell death (Bellavite and hensive studies of the antiviral activity of polyphenols against the SARS-
Donzelli, 2020). CoV-2 coronavirus could provide an additional strategy, for example as
Viral infection disrupts the defensive antioxidant mechanism of a curative treatment in vaccines, to combat this pandemic that is caus-
the human body, bringing inflammation and oxidative damage. ing the deadly disease 2019-nCovid.
10
Declaration of competing interest Chiow, K.H., Phoon, M.C., Putti, T., Tan, B.K.H., Chow, V.T., 2016. Evaluation of antiviral ac-
tivities of Houttuynia cordata thunb. extract, quercetin, quercetrin and cinanserin on
murine coronavirus and dengue virus infection. Asian Pac J Trop Med 9, 1–7. https://
The authors declare that they have no known competing financial doi.org/10.1016/j.apjtm.2015.12.002.
interests or personal relationships that could have appeared to influ- Choi, H.J., Song, J.H., Bhatt, L.R., Baek, S.H., 2010. Anti-human rhinovirus activity of gallic
acid possessing antioxidant capacity. Phyther. Res. 24, 1292–1296. https://doi.org/
ence the work reported in this paper. 10.1002/ptr.3101.
Chojnacka, K., Witek-Krowiak, A., Skrzypczak, D., Mikula, K., Mlynarz, P., 2020. Phyto-
Acknowledgements chemicals containing biologically active polyphenols as an effective agent against
Covid-19-inducing coronavirus. J. Funct. Foods 73. https://doi.org/10.1016/j.jff.2020.
104146.
This research was supported by the R2MIT project (CTM2017- Cohen, J.I., 2018. Vaccine development for Epstein-Barr virus. Human Herpesviruses. Ad-
85346-R) financed by the Spanish Ministry of Economy and Competi- vances in Experimental Medicine and Biology. Springer, Singapore, pp. 477–493
tiveness (MINECO) and by the Catalan Government (ref. 2017-SGR- https://doi.org/10.1007/978-981-10-7230-7_22.
Cory, H., Passarelli, S., Szeto, J., Tamez, M., Mattei, J., 2018. The role of polyphenols in
312), Spain. María Fernanda Montenegro-Landívar thanks MINECO for human health and food systems: a mini-review. Front. Nutr. 5, 1–9. https://doi.org/
her predoctoral fellowship (ref. PRE2018-083861). Paulina Tapia- 10.3389/fnut.2018.00087.
Quirós thanks to The National Council of Science and Technology of Crawford, S.E., Ramani, S., Tate, J.E., Parashar, U.D., Svensson, L., Hagbom, M., Franco, M.A.,
Greenberg, H.B., O’Ryan, M., Kang, G., Desselberger, U., Estes, M.K., 2017. Rotavirus in-
Mexico (CONACYT) for her predoctoral fellowship. Xanel Vecino ac- fection. Nat. Rev. Dis. Prim. 3. https://doi.org/10.1038/nrdp.2017.83.
knowledges Spanish Ministry of Science and Innovation for her financial Cushnie, T.P.T., Lamb, A.J., 2005. Antimicrobial activity of flavonoids. Int. J. Antimicrob.
support under the project PID2019-103873RJ-I00. Agents 26, 343–356. https://doi.org/10.1016/j.ijantimicag.2005.09.002.
Da Silva Antonio, A., Moreira Wiedemann, L.S., Veiga-Junior, V.F., 2020. Natural products’
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Science of the Total Environment 801 (2021) 149719

Contents lists available at ScienceDirect

Science of the Total Environment

journal homepage: www.elsevier.com/locate/scitotenv

Polyphenols and their potential role to ﬁght viral diseases: An overview

• Fruits and vegetables residues are a nat-

1. Introduction often damages or destroys infected cells, causing a viral disease

(continued on next page)

zoster and acute pain in latently infected

properties against viral diseases. Additionally, the extraction, puriﬁca- Table 2

Plant source Polyphenol Type of virus Reference

Polyphenol Source Mechanism of action Analysis Reference

Antiviral polyphenol Plant source Study Virus type Main mechanism

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