key: cord-0874757-ef90qb20
authors: Di Petrillo, Amalia; Orrù, Germano; Fais, Antonella; Fantini, Massimo C.
title: Quercetin and its derivates as antiviral potentials: A comprehensive review
date: 2021-10-28
journal: Phytother Res
DOI: 10.1002/ptr.7309
sha: 232942658bb5dd874831a7c2be842330b1565012
doc_id: 874757
cord_uid: ef90qb20

Quercetin, widely distributed in fruits and vegetables, is a flavonoid known for its antioxidant, antiviral, antimicrobial, and antiinflammatory properties. Several studies highlight the potential use of quercetin as an antiviral, due to its ability to inhibit the initial stages of virus infection, to be able to interact with proteases important for viral replication, and to reduce inflammation caused by infection. Quercetin could also be useful in combination with other drugs to potentially enhance the effects or synergistically interact with them, in order to reduce their side effects and related toxicity. Since there is no comprehensive compilation about antiviral activities of quercetin and derivates, the aim of this review is providing a summary of their antiviral activities on a set of human viral infections along with mechanisms of action. Thus, the following family of viruses are examined: Flaviviridae, Herpesviridae, Orthomyxoviridae, Coronaviridae, Hepadnaviridae, Retroviridae, Picornaviridae, Pneumoviridae, and Filoviridae.

plant constituents have been approved so far. The reason could be the problematic assessing of the safety and effectiveness of herbal medicines, due to herbal adverse events and herb-drug interactions (Izzo et al., 2016) .

A strategy could be to enhance people's antiviral immune response through a nutritious diet including pure quercetin, isolated from natural extracts, in order to minimize the risk of infections.

Recently, quercetin has been used as adjuvant therapy in symptomatic patients and the result was an improvement in clinical symptoms and a reduction in length of hospitalization .

This review aims to collect and present the current knowledge of the antiviral property of quercetin and its mechanisms of action, focusing the attention on the major human viruses belonging to families of Flaviviridae, Herpesviridae, Orthomyxoviridae, Coronaviridae, Hepadnaviridae, Retroviridae, Picornaviridae, Pneumoviridae, and Filoviridae.

Flaviviridae is a family of enveloped positive-strand RNA viruses. The family includes the genera of Flavivirus, Pestivirus, Hepacivirus, and

Pegivirus. Hepatitis C virus belongs to the Hepacivirus genus and is the major cause of viral hepatitis, with an estimated 71.1 million individuals chronically infected worldwide (Roudot-Thoraval, 2021) . Treatment with direct-acting antivirals drugs has dramatically changed outcomes of hepatitis C. Indeed, the sustained viral response rates have reached unprecedented levels (>95%) without relevant adverse events (Kowdley et al., 2014; Webster et al., 2015) . However, the price is still one of the major barriers to achieve hepatitis C eradication mainly in low-and middle-income countries.

Several studies, summarized in Table 1 , show the role of quercetin as an antiviral against HCV, in which it was reported that quercetin acts at different levels.

Recently, in vitro studies performed on cells have identified the possible interaction of quercetin with HCV's nonstructural (NS) protein. Khachatoorian et al. (2012) , tested the flavonoid for their antiviral activity using the HCV cell culture system treating it 3 h after infection. The study showed how quercetin markedly blocks viral translation, completely blocks NS5A-augmented Internal Ribosome Entry Site (IRES)-mediated translation in an IRES reporter assay and inhibits HSP70 induction, assuming that the antiviral activity of quercetin is mediated through different mechanisms (Khachatoorian et al., 2012) .

Moreover, the inhibitory effect of quercetin was also obtained using a model system in which NS3 engineered substrates were introduced in NS3-expressing cells, providing evidence that inhibition could be directed to the NS3. In particular, these cells expressed only NS3 protease and did not carry additional HCV sequences, neither NS5A activities nor IRES translation (Bachmetov et al., 2012) . In another study, quercetin showed a marked anti-HCV activity in replicon containing cells when combined with interferon (IFN)α. Quercetin decreased HCV-induced reactive oxygen and nitrogen species (ROS/RNS) generation and lipoperoxidation in replicating cells. Quercetin also inhibited liver X receptor (LXR) α-induced lipid accumulation in LXRα-overexpressing and replicon-containing Huh7 cells. This activity might contribute to the inhibitory effect of quercetin on HCV replication (Pisonero-Vaquero et al., 2014) . The effect of quercetin on the expression of key genes involved in lipid metabolism was confirmed by other studies. In particular, quercetin appears to reduce diglyceride acyltransferase 1 (DGAT1) mRNA expression increased by viral infection. Since HCV particle formation requires DGAT1, this could be another quercetin mechanism of action (Rojas et al., 2016) . Molecular docking, increasingly used for the research of new drugs, provides that quercetin and its derivates can establish key coordination with NS5B, an RNA-dependent RNA polymerase, by two magnesium ions as well as interactions with residues at the active site (Zhong et al., 2015) , this gives further evidence to previous studies in which N5 was the protagonist of a possible mechanism of action on HCV inhibition. Meanwhile, another molecular docking study showed that quercetin is a potential inhibitor of NS2 protease (Sajitha Lulu (Whitley, 1996) . Therapies that can target the latent phase of these viral infections could potentially result in eradication.

It has long been known that quercetin and derivates show antiviral effect on Herpesviridae, particularly HSV-1 and HSV-2 (Table 2 ).

In vitro studies showed the reduction of intracellular replication of HSV1-2 and human cytomegalovirus (HCMV) when cell monolayers were infected and subsequently cultured in medium containing quercetin, instead preincubation of tissue culture cell monolayers with quercetin did not affect the ability of the viruses to infect or replicate in the tissue culture monolayers.

Quercetin showed antiviral activity toward HCMV infected cells in a concentration of 4.8 μM. It was found that quercetin partially inhibited the production of Immediate Early Protein and strongly inhibited Early Protein production, suggesting that the flavonol operates at a time point between immediate early and early protein expression (Cotin et al., 2012) .

To evaluate the anti-HSV-1 effect of quercetin, Raw 264.7 cells were infected with HSV-1 at 0.1 multiplicity of infection (MOI) in presence or absence of quercetin. In another set of experiment cells were first infected with HSV-1 at 0.1 MOI and, 2 h later, quercetin was added. In both cases a similar decrease in plaque formation was found (50% decrease for 10 μg/ml). In order to find the molecular mechanism responsible for the anti-HSV-1 effect, western blotting Quercetin and isoquercitrin displayed potent antiviral activities against both VZV and HCMV. Both compounds strongly suppressed the expression of lytic immediate-early genes (IEG) .

Nevertheless, Hung et al., (2015) , have shown how Houttuynia cordata water extract, which has quercetin and isoquercetin among the major components, has an antiviral activity against HSV-1 and HSV-2 and is HSV aciclovir resistant (HSV-AR). To elucidate the mechanism of action, cells infected with 100 pfu of the viruses were co-treated or pretreated with the extract. Pretreatment showed that plaque formation was largely inhibited, assuming that the anti-HSV effects of the extract might target virus particles directly and inhibit further stages of HSV infection. In the co-treatment, on the other hand, the extract inhibited HSV-1, HSV-2, and HSV-AR binding ability in a dose-dependent manner. By analyzing the major components, it was found, that quercetin and isoquercetin targeted virus particles directly and inhibited viral entry. Furthermore, it was identified that both isoquercitin and quercetin inhibited NF-κB activation in HSV infection (Hung et al., 2015) .

Regarding EBV, latent EBV infection can lead to serious malignancies, such as, Burkitt's lymphoma, Hodgkin's disease, and gastric carcinoma, and EBV associated gastric carcinoma is one of the most common EBV-associated cancers.

In vitro study performed on EBV-driven B cell immortalization showed that quercetin inhibits the activation of signal transducer and activator of transcription 3 (STAT3) induced by EBV infection and reduce molecules such as interleukin-6 (IL-6) and ROS known to be essential for the immortalization process. Moreover, it was found that quercetin promoted autophagy and counteracted the accumulation of sequestosome1/p62, ultimately leading to the prevention of B cell immortalization. These findings suggest that quercetin may have the potential to be used to counteract EBV-driven lymphomagenesis, especially if its stability is improved (Granato et al., 2019) .

These results indicate that quercetin could be a promising candidate anti-HSV and HSV-AR since its mechanism of action seems to be able to bind the virus in the early stages and prevent its entry.

The Orthomyxoviridae is a family of viruses that possesses seg- Natural products appear to be a major source of anti-influenza drug discovery and offer new prospects for influenza management.

A activity of quercetin and derivates (Table 3) suggest that the antiviral mechanism of isoquercetin may involve early stages of viral replication (Kim et al., 2010) . The antiviral activity of quercetin and isoquercetin was also confirmed by a subsequent study by the same authors (Thapa et al., 2012) .

A quercetin derivative, quercetin-3-O-α-L-rhamnopyranoside (Q3R), isolated from Rapanea melanophloeos, was able to significantly decrease copy numbers of M2 and NP genes in co-penetration treatment, which confirms the blockage of the viral particle receptors from penetration inside the cell. Thus, fewer viral particles propagated inside the cell. No significant effect in pre-and post-penetration treatments verified the inability of the compound to influence the cellular receptors and probably the cellular pathways. Moreover, the study revealed that Q3R, especially in the co-penetration treatment, alters the status of cytokine production, increasing the IL-27 production significantly, which has antiinflammatory properties, and decreasing the TNF-α production, a pro-inflammatory substance (Mehrbod et al., 2018) . In vivo study on mouse model of influenza virus, showed how quercetin derivatives significant decreased mortality, reduced the levels of IFN-γ, iNOS, and RANTES in the lungs compared to the untreated group and histological evaluation showed that delayed the development and progression of pulmonary lesions (Choi et al., 2012; Kim et al., 2010; Liu et al., 2016) .

Molecular docking studies showed the potential target of quercetin. In a study, quercetin appears to have a high binding potential to NA comparable with oseltamivir and zanamivir. In a first study, 

Coronaviridae is a family of enveloped and positive-strand RNA viruses, which includes two subfamilies: Coronavirinae and

Torovirinae (Payne, 2017) . Human coronaviruses, such as HCoV-229E

and HCoV-OC43, have long been known to circulate in the population and they, together with the more recently identified HCoV-NL63 and Recently several articles have been published on quercetin and its ability to protect against coronaviruses (Table 4) Another coronavirus target is viral the spike protein (S protein). In fact, a reasonable target for structure-based drug discovery was identified to be the disruption of the viral S protein-angiotensin-converting enzyme 2 (ACE2) receptor interface. A computational model of the S-protein of SARS-CoV-2 interacting with the human ACE2 receptor was used to identify small molecules to potentially limit viral recognition of host cells and/or to disrupt host-virus interactions (Smith & Smith, 2020) . 

Hepadnaviridae is a family of small, enveloped viruses with partially double-stranded DNA. It contains two genera: hepatitis viruses, specific for man and other mammals, are grouped in the genus Orthohepadnavirus, while those of birds are placed into the genus Avihepadnavirus.

classified into eight genotypes today and numerous subgenotypes (Schaefer, 2007) .

Nearly 350 million people are chronically infected with HBV in the world, which is one of major global health problems. It is estimated that about 780,000 people die each year due to consequences of hepatitis B (HB), such as liver cirrhosis and liver cancer ("Hepatitis B," 2021). Current treatments include nucleoside/nucleotide analog therapy and interferon therapy. Long-term, nucleoside/nucleotide analog therapy often leads to drug resistance, and interferon therapy can be used only for a limited duration due to its many side effects (Zoulim & Locarnini, 2009 ). B can be prevented by vaccines that are safe, available, and effective ("Hepatitis B," 2021).

F I G U R E 1 Molecular interactions between Quercetin-3-β-galactoside and SARS-CoV-2 3CLpro. Note: Quercetin-3-β-galactoside forms hydrogen bonds specifically with Gln189 and Glu166 amino acids located inside a specific pocket hollowed in 3CLpro surface. The threedimensional (3D) protein structures were created by using SWISS MODEL program [Colour figure can be viewed at wileyonlinelibrary.com] Several in vitro studies shown how quercetin inhibits HBV antigen, Hepatitis B surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg), secretion and genome replication in human hepatoma cell lines (Table 5) , which suggests that quercetin may be a potentially effective anti-HBV agent (Alam et al., 2017; Cheng et al., 2015) . (Parvez et al., 2020) .

These in vitro studies show how quercetin can block HBV replication by acting on HBsAg, HBeAg, HBV polymerase, and Core protein.

The family Retroviridae is a large family of RNA viruses that replicate through a DNA intermediate. It is divided into two subfamilies (Orthoretrovirinae and Spumaretrovirinae) and seven genera (Ryu, 2017) . Since the mid 1980s, retroviruses have been the focus of an intensive research effort, due primarily to the causative association between the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome (AIDS).

Highly active antiretroviral therapy (HAART) is a medication regimen used in the management and treatment of human immunodeficiency virus type 1 (HIV-1). However, the treatment is required to be administered for the remainder of an individual's lifetime due to latent HIV-1 reservoirs. The "shock and kill" strategy, which involves using agents to reactivate latent HIV-1 and subsequently killing latently infected cells in the presence of HAART, was recently proposed.

Unfortunately, the agents used showed a high toxicity. Therefore, the identification of novel latency activators is required (Yang et al., 2018) .

In vitro enzyme inhibitory properties showed a quercetin inhibition power against HIV-1 integrase (HIV-1 IN) and topoisomerase II with IC 50 11.0 and 19.4 μM respectively (Fesen et al., 1993) . In conclusion, as shown in Table 6 , quercetin seems to inhibit in vitro HIV-1 replication acting on integrase and topoisomerase II;

however, these results need to be confirmed in other studies to fully demonstrate its inhibitory potential.

Picornaviruses are small, nonenveloped, icosahedral RNA viruses with positive-strand polarity. Although many of picornavirus infections remain asymptomatic, some are important human and animal pathogens and cause diseases that affect different tissues. Genera associated with Picornaviridae include erbovirus, teschovirus, kobuvirus, aphthovirus, cardiovirus, enterovirus, coxsackievirus, hepatovirus, parechovirus, and rhinovirus (Zell, 2018) . Quercetin and derivatives seem to inhibit Picornaviridae family by acting on early stage of virus replication, even in this case the maximum antiviral activity was found by treating the cells with quercetin after they were infected or during the infection. Furthermore, the ability to inhibit pro-inflammatory cytokines, hence the ability of quercetin to act on the immune system, was observed also in this case.

In Table 7 the summary of the antiviral activity against picornavirus is reported.

The family Pneumoviridae comprises large enveloped negative-sense RNA viruses. This family has two genera, Orthopneumovirus and

Metapneumovirus. Some viruses are specific and pathogenic for humans, such as human respiratory syncytial virus (RSV) and human metapneumovirus (Rima et al., 2017) .

HumanRSV causes a globally prevalent respiratory infection, which can cause life-threatening illness, particularly in the young, elderly, and immunocompromised. The mainstay of treatment for patients with RSV is supportive care.

Several studies investigated the quercetin mechanism of action by molecular docking (Table 8) 

Protein 1 (NS1)-quercetin interaction. NS1 is an RSV non-structural protein plays an important role in the modulation of the host response to infection, antagonizing the interferon-mediated antiviral state (Atreya et al., 1998) . Experimental and in silico approaches showed that the interaction between RSV-NS1 and quercetin is stable, with a dissociation constant of the order of 10 À6 M. Thus, NS1 could be a quercetin potential target (Gomes et al., 2016) .

Other research suggest that quercetin and its derivatives exert their action by interacting with the M2-1 protein, involved in genome replication and transcription by form the complex RNA-dependent RNA polymerase. Molecular docking showed that these compounds could interact with M2-1 in important domains for its activity (Guimarães et al., 2018; Teixeira et al., 2017) . (Komaravelli et al., 2015) .

In conclusion quercetin could experts its antiviral action interacting with structural and non-structural protein and reducing proinflammatory cytokines. (He et al., 2015) .

Like showed in cells than in Vero cells might suggest a dual mechanism of action:

impairing the IFN antagonism of VP24 and blocking virus entry (Fanunza et al., 2020) .

Quercetin could inhibit the first stage of infection interacting with structural protein and reducing anti-IFN function of VP24. However, furthers and in vivo studies are needed.

Quercetin and its derivatives are naturally occurring phytochemicals with promising bioactive effects such as immunoprotective, antiinflammatory, and antiviral effects. In this review the antiviral activity of quercetin and its derivates against potential human viruses was collected. Quercetin showed a potent antiviral activity in vitro and the different mechanisms of action are reported in Figure 2 .

Particularly, quercetin seems to block virus entry by interacting with membrane glycoproteins such as gD of HSV and NA of H1N1.

Moreover, molecular docking studies have shown that quercetin and its derivatives could interact with specific proteases essential for viral replication, such as NS2, NS3, and NS5A of HCV, integrase and TOP2 of HIV, Mpro of Coronaviridae, and 3Cpro of Enterovirus.

All these studies shown how the quercetin and its derivates have a wide spectrum of antiviral activities and a better understanding of quercetin's mechanistic properties could help in the rational design of more potent or bioavailable flavonol-type compounds.

Despite many in vitro studies, there are very low studies with human subjects. It would be of extreme importance to pay attention to the use of quercetin for preventive purposes, as well as in combination with drugs, in order to enhance or synergistically interact with these chemical agents and consequently reduce their side effects, related toxicity, and increase their overall efficacy and safety.

Authors declare no conflict of interest.

The data that support the findings of this study are openly available in 

Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening

Quercetin: Antiviral significance and possible COVID-19 integrative considerations

Beneficial effects of quercetin on obesity and diabetes

Quantitative analysis of rutin, quercetin, naringenin, and gallic acid by validated RP-and NP-HPTLC methods for quality control of anti-HBV active extract of Guiera senegalensis

The NS1 protein of human respiratory syncytial virus is a potent inhibitor of minigenome transcription and RNA replication

Quercetin/βcyclodextrin inclusion complex embedded nanofibres: Slow release and high solubility

Suppression of hepatitis C virus by the flavonoid quercetin is mediated by inhibition of NS3 protease activity

The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic β-cells, glycemic control and inflammation: In vitro and in vivo studies

Quercetin and derivatives: Useful tools in inflammation and pain management

Anti-HIV-1 integrase compounds from Dioscorea bulbifera and molecular docking study

Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CLpro: Structure-activity relationship studies reveal salient pharmacophore features

Inhibition of hepatitis B virus replication by quercetin in human hepatoma cell lines

Quercetin 3-rhamnoside exerts antiinfluenza A virus activity in mice

Eight flavonoids and their potential as inhibitors of human cytomegalovirus replication

COVID-19 treatments: authorisedjEuropean Medicines Agency

Effects of propolis flavonoids on virus infectivity and replication

A role for quercetin in coronavirus disease 2019 (COVID-19)

Broad-range potential of Asphodelus microcarpus leaves extract for drug development

Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: A prospective, randomized, controlled, and open-label study

Quercetin blocks ebola virus infection by counteracting the VP24 interferon-inhibitory function

Inhibitors of human immunodeficiency virus integrase

Virus-inhibiting activity of dihydroquercetin, a flavonoid from Larix sibirica, against coxsackievirus B4 in a model of viral pancreatitis

Quercetin inhibits rhinovirus replication in vitro and in vivo

Probing the impact of quercetin-7-O-glucoside on influenza virus replication influence

New insights into antiviral and cytotoxic potential of quercetin and its derivatives-A biochemical perspective

Experimental evidence and molecular modeling of the interaction between hRSV-NS1 and quercetin

Quercetin interrupts the positive feedback loop between STAT3 and IL-6, promotes autophagy, and reduces ROS, preventing EBV-driven B cell immortalization

Binding investigation between M2-1protein from hRSV and acetylated quercetin derivatives: 1H NMR, fluorescence spectroscopy, and molecular docking

Endogenous and exogenous mediators of quercetin bioavailability

Filovirus RNA in fruit bats, China. Emerging Infectious Diseases

The COVID-19 pandemic: A comprehensive review of taxonomy, genetics, epidemiology, diagnosis, treatment, and control

Houttuynia cordata targets the beginning stage of herpes simplex virus infection

A critical approach to evaluating clinical efficacy, adverse events and drug interactions of herbal remedies

Inhibition of SARS-CoV 3CL protease by flavonoids

Quercetin and related polyphenols: New insights and implications for their bioactivity and bioavailability. Food and Function

Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle

Antiviral activities of quercetin and isoquercitrin against human herpesviruses

Inhibition of influenza virus replication by plant-derived isoquercetin

Role of dietary antioxidants in human metapneumovirus infection

Ledipasvir and Sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis

The anti-HSV-1 effect of quercetin is dependent on the suppression of TLR-3 in raw 264.7 cells

Computational screen and experimental validation of anti-influenza effects of quercetin and chlorogenic acid from traditional Chinese medicine

Molecular docking of potential inhibitors for influenza H7N9

Quercetin pentaacetate inhibits in vitro human respiratory syncytial virus adhesion

A phase i dose escalation study demonstrates quercetin safety and explores potential for bioflavonoid antivirals in patients with chronic hepatitis C

Resistance of influenza viruses to neuraminidase inhibitors-A review

Immunomodulatory properties of quercetin-3-O-α-L-rhamnopyranoside from Rapanea melanophloeos against influenza a virus

Inhibitory activity of quercetin, its metabolite, and standard antiviral drugs towards enzymes essential for SARS-CoV-2: The role of acid-base equilibria

Viral M2 ion channel protein: A promising target for anti-influenza drug discovery

Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris

Estimated daily intake and seasonal food sources of quercetin in Japan

Bioassay-guided isolation of anti-hepatitis B virus flavonoid myricetin-3-O-rhamnoside along with quercetin from Guiera senegalensis leaves

Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: Cell culture and molecular docking study

Family coronaviridae

Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

Prophylactic efficacy of quercetin 3-β-O-D-glucoside against Ebola virus infection

Flavonoids as multi-target inhibitors for proteins associated with Ebola virus: In silico discovery using virtual screening and molecular docking studies

Anticancer potential of quercetin: A comprehensive review

ICTV virus taxonomy profile: Pneumoviridae

Effect of quercetin on Hepatitis C virus life cycle: From viral to host targets

Epidemiology of hepatitis C virus infection

Retroviruses. Molecular Virology of Human Pathogenic Viruses

Docking study of flavonoid derivatives as potent inhibitors of influenza H1N1 virus neuraminidas

Antiinflammatory potential of quercetin in COVID-19 treatment

Naringenin and quercetin-Potential anti-HCV agents for NS2 protease targets

Hepatitis B virus genotypes in Europe

Dual resistance to adamantanes and oseltamivir among seasonal influenza A(H1N1) viruses: 2008-2010

Inhibitory effect of flavonoids on DNA-dependent DNA and RNA polymerases

Quercetin-resveratrol combination for prostate cancer management in TRAMP mice

Repurposing therapeutics for COVID-19: Supercomputer-based docking to the SARS-CoV-2 viral spike protein and viral spike protein-human ACE2 interface

A review of neuraminidase inhibitor susceptibility in influenza strains

Inhibition of reverse transcriptases by flavonoids

Biophysical characterization of the interaction between M2-1 protein of hRSV and quercetin

Pathogenesis of Middle East respiratory syndrome coronavirus

Antiviral ability of Kalanchoe gracilis leaf extract against enterovirus 71 and coxsackievirus A16. Evidence-Based Complementary and Alternative Medicine

SWISS-MODEL: Homology modelling of protein structures and complexes

Hepatitis C

Herpesviruses. Diseases of Swine

Progress of small molecular inhibitors in the development of anti-influenza virus agents

Antioxidant activities of quercetin and its complexes for medicinal application

Quercetin synergistically reactivates human immunodeficiency virus type 1 latency by activating nuclear factor-κB

Inhibition of enterovirus 71 replication and viral 3C protease by quercetin

Picornaviridae-The ever-growing virus family

Molecular mechanism of functional ingredients in barley to combat human chronic diseases

Discovery of metal ions chelator quercetin derivatives with potent anti-HCV activities

Hepatitis B virus resistance to nucleos(t) ide analogues

Quercetin and its derivates as antiviral potentials: A comprehensive review