Quercetin in the Prevention and Treatment of Coronavirus Infections: A Focus on SARS-CoV-2
Amin Gasmi, Pavan Kumar Mujawdiya, Roman Lysiuk, Mariia Shanaida, Massimiliano Peana, Asma Gasmi Benahmed, Nataliya Beley, Nadiia Kovalska, Geir Bjørklund
Pharmaceuticals, doi:10.3390/ph15091049
The COVID-19 outbreak seems to be the most dangerous challenge of the third millennium due to its highly contagious nature. Amongst natural molecules for COVID-19 treatment, the flavonoid molecule quercetin (QR) is currently considered one of the most promising. QR is an active agent against SARS and MERS due to its antimicrobial, antiviral, anti-inflammatory, antioxidant, and some other beneficial effects. QR may hold therapeutic potential against SARS-CoV-2 due to its inhibitory effects on several stages of the viral life cycle. In fact, QR inhibits viral entry, absorption, and penetration in the SARS-CoV virus, which might be at least partly explained by the ability of QR and its derivatives to inhibit 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro). QR is a potent immunomodulatory molecule due to its direct modulatory effects on several immune cells, cytokines, and other immune molecules. QR-based nanopreparations possess enhanced bioavailability and solubility in water. In this review, we discuss the prospects for the application of QR as a preventive and treatment agent for COVID-19. Given the multifactorial beneficial action of QR, it can be considered a very valid drug as a preventative, mitigating, and therapeutic agent of COVID-19 infection, especially in synergism with zinc, vitamins C, D, and E, and other polyphenols.
References
Adem, Eyupoglu, Sarfraz, Rasul, Ali, Identification of potent COVID-19 main protease (Mpro) inhibitors from natural polyphenols: An in silico strategy unveils a hope against CORONA, Preprints,
doi:10.20944/preprints202003.0333.v1Almeida, Borge, Piskula, Tudose, Tudoreanu et al., Bioavailability of Quercetin in Humans with a Focus on Interindividual Variation, Compr. Rev. Food Sci. Food Saf,
doi:10.1111/1541-4337.12342Amoros, Simoes, Girre, Sauvager, Cormier, Synergistic effect of flavones and flavonols against herpes simplex virus type 1 in cell culture. Comparison with the antiviral activity of propolis, J. Nat. Prod,
doi:10.1021/np50090a003Aslam, Jahan, Rahman, Zafar, Ashraf, Synergistic interactions of polyphenols and their effect on antiradical potential, Pak. J. Pharm. Sci
Aucoin, Cooley, Saunders, Cardozo, Remy et al., The effect of quercetin on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review, Adv. Integr. Med,
doi:10.1016/j.aimed.2020.07.007Bastaminejad, Bakhtiyari, Quercetin and its relative therapeutic potential against COVID-19: A retrospective review and prospective overview, Curr. Mol. Med,
doi:10.2174/1566524020999200918150630Biancatelli, Berrill, Catravas, Marik, Quercetin, Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19), Front. Immunol,
doi:10.3389/fimmu.2020.01451Biswas, Does the Interdependence between Oxidative Stress and Inflammation Explain the Antioxidant Paradox? Oxid, Med. Cell Longev,
doi:10.1155/2016/5698931Bjørklund, Dadar, Chirumbolo, Lysiuk, Flavonoids as detoxifying and pro-survival agents: What's new?, Food Chem. Toxicol,
doi:10.1016/j.fct.2017.10.039Chen, Li, Luo, Liu, Xu et al., Binding interaction of quercetin-3-beta-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): Structure-activity relationship studies reveal salient pharmacophore features, Bioorg. Med. Chem,
doi:10.1016/j.bmc.2006.09.014Chen, Lin, Huang, Chen, Hsieh et al., Inhibition of SARS-CoV 3C-like Protease Activity by Theaflavin-3,3'-digallate (TF3), Evid. Based Complement Alternat Med,
doi:10.1093/ecam/neh081Chiow, Phoon, Putti, Tan, Chow, Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection, Asian Pac. J. Trop. Med,
doi:10.1016/j.apjtm.2015.12.002Chirumbolo, Bjorklund, Lysiuk, Vella, Lenchyk et al., Targeting Cancer with Phytochemicals via Their Fine Tuning of the Cell Survival Signaling Pathways, Int. J. Mol. Sci,
doi:10.3390/ijms19113568Chirumbolo, The role of quercetin, flavonols and flavones in modulating inflammatory cell function, Inflamm. Allergy Drug Targets,
doi:10.2174/187152810793358741Cho, Curtis-Long, Lee, Kim, Ryu et al., Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa, Bioorg. Med. Chem,
doi:10.1016/j.bmc.2013.03.027Crisponi, Nurchi, Lachowicz, Peana, Medici et al., Chapter 18-Toxicity of Nanoparticles: Etiology and Mechanisms
David, Arulmoli, Parasuraman, Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid, Pharm. Rev,
doi:10.4103/0973-7847.194044Day, Canada, Diaz, Kroon, Mclauchlan et al., Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase, FEBS Lett
Delvecchio, Vadrucci, Cavalcanti, De Santis, Kunde et al., Polyphenol administration impairs T-cell proliferation by imprinting a distinct dendritic cell maturational profile, Eur. J. Immunol,
doi:10.1002/eji.201545679Derosa, Maffioli, D'angelo, Di Pierro, A role for quercetin in coronavirus disease 2019 (COVID-19), Phytother. Res,
doi:10.1002/ptr.6887El-Rahmanand, Suhailah, Quercetin nanoparticles: Preparation and characterization, Indian J. Drugs
Gao, Liu, Wang, Liu, Xu et al., Preparation of a chemically stable quercetin formulation using nanosuspension technology, Int. J. Pharm,
doi:10.1016/j.ijpharm.2010.11.009Garcia-Mediavilla, Crespo, Collado, Esteller, Sanchez-Campos et al., The antiinflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells, Eur. J. Pharmacol,
doi:10.1016/j.ejphar.2006.11.014Gasmi, Noor, Tippairote, Dadar, Menzel et al., Individual risk management strategy and potential therapeutic options for the COVID-19 pandemic, Clin. Immunol,
doi:10.1016/j.clim.2020.108409Gasmi, Tippairote, Mujawdiya, Peana, Menzel et al., Micronutrients as immunomodulatory tools for COVID-19 management, Clin. Immunol,
doi:10.1016/j.clim.2020.108545Geoghegan, Tsui, Wong, Rabie, Inhibitory effect of quercetin on periodontal pathogens, Ann. R. Australas. Coll. Dent. Surg
Glinsky, Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells, Biomedicines,
doi:10.3390/biomedicines8050129Gonzalez-Burquez, Gonzalez-Diaz, Garcia-Tovar, Carrillo-Miranda, Soto-Zarate et al., Comparison between In Vitro Antiviral Effect of Mexican Propolis and Three Commercial Flavonoids against Canine Distemper Virus, Evid. Based Complement Alternat Med,
doi:10.1155/2018/7092416Gupta, Kumar, Gupta, Sharma, Verma et al., Reversion of Asthmatic Complications and Mast Cell Signalling Pathways in BALB/c Mice Model Using Quercetin Nanocrystals, J. Biomed. Nanotechnol,
doi:10.1166/jbn.2016.2197Halder, Mukherjee, Ghosh, Mandal, Chatterji et al., Smart PLGA nanoparticles loaded with Quercetin: Cellular uptake and in-vitro anticancer study, Mater. Today,
doi:10.1016/j.matpr.2017.10.156Han, Wang, Cai, Liu, Zhang et al., Quercetin nanoparticles with enhanced bioavailability as multifunctional agents toward amyloid induced neurotoxicity, J. Mater. Chem. B,
doi:10.1039/C7TB03053CHashemzaei, Delarami Far, Yari, Heravi, Tabrizian et al., Anticancer and apoptosis-inducing effects of quercetin in vitro and in vivo, Oncol. Rep
Hecel, Ostrowska, Stokowa-Soltys, Watly, Dudek et al., Zinc(II)-The Overlooked Eminence Grise of Chloroquine's Fight against COVID-19?, Pharmaceuticals,
doi:10.3390/ph13090228Heeba, Mahmoud, El Hanafy, Anti-inflammatory potential of curcumin and quercetin in rats: Role of oxidative stress, heme oxygenase-1 and TNF-alpha, Toxicol. Ind. Health,
doi:10.1177/0748233712462444Hirai, Okuno, Katsuma, Arita, Tachibana et al., Characterisation of anti-Staphylococcus aureus activity of quercetin, Int. J. Food Sci. Technol,
doi:10.1111/j.1365-2621.2010.02267.xHsu, Compounds Derived from Epigallocatechin-3-Gallate (EGCG) as a Novel Approach to the Prevention of Viral Infections, Inflamm. Allergy Drug Targets,
doi:10.2174/1871528114666151022150122Imran, Thabet, Alaqel, Alzahrani, Abida et al., The Therapeutic and Prophylactic Potential of Quercetin against COVID-19: An Outlook on the Clinical Studies, Inventive Compositions, and Patent Literature, Antioxidants,
doi:10.3390/antiox11050876Jaganathan, Mandal, Antiproliferative effects of honey and of its polyphenols: A review, J. Biomed. Biotechnol,
doi:10.1155/2009/830616Jeevanandam, Barhoum, Chan, Dufresne, Danquah, Review on nanoparticles and nanostructured materials: History, sources, toxicity and regulations, Beilstein. J. Nanotechnol,
doi:10.3762/bjnano.9.98Jo, Kim, Kim, Shin, Kim, Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors, Chem. Biol. Drug Des,
doi:10.1111/cbdd.13604Kaihatsu, Yamabe, Ebara, Antiviral Mechanism of Action of Epigallocatechin-3-O-gallate and Its Fatty Acid Esters, Molecules,
doi:10.3390/molecules23102475Khaerunnisa, Kurniawan, Awaluddin, Suhartati, Soetjipto, Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study, Preprints,
doi:10.20944/preprints202003.0226.v1Kim, Seo, Curtis-Long, Oh, Oh et al., Phenolic phytochemical displaying SARS-CoV papain-like protease inhibition from the seeds of Psoralea corylifolia, J. Enzyme. Inhib. Med. Chem
Kuzmenko, Pavlyuchenko, Tumanovskaya, Dosenko, Moybenko, Experimental therapy of cardiac remodeling with quercetin-containing drugs, Patol. Fiziol. Eksp. Ter
Lin, Tsai, Tsai, Lai, Wan et al., Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds, Antiviral. Res,
doi:10.1016/j.antiviral.2005.07.002Liu, Raghuvanshi, Ceylan, Bolling, Quercetin and Its Metabolites Inhibit Recombinant Human Angiotensin-Converting Enzyme 2 (ACE2) Activity, J. Agric. Food Chem,
doi:10.1021/acs.jafc.0c05064Liu, Zhou, Li, Garner, Watkins et al., Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases, ACS Cent. Sci,
doi:10.1021/acscentsci.0c00272Lutai, Parkhomeko, Ryzhkova, Havrylenko, Irkin et al., Effects of Intravenous 5-Lipoxygenase Inhibitor Quercetin Therapy on Endothelial Function, Severity of Systemic Inflammation and Oxidative Stress in Acute ST Elevation Myocardial Infarction, Emerg. Med,
doi:10.22141/2224-0586.1.72.2016.74473Lysiuk, Hudz, Differential spectrophotometry: Application for quantification of flavonoids in herbal drugs and nutraceuticals, Int. J. Trends Food Nutr
Maturu, Wei-Liang, Androutsopoulos, Jiang, Wang et al., Quercetin attenuates the hyperoxic lung injury in neonatal mice: Implications for Bronchopulmonary dysplasia (BPD), Food Chem. Toxicol
Mehany, Khalifa, Barakat, Althwab, Alharbi et al., Polyphenols as promising biologically active substances for preventing SARS-CoV-2: A review with research evidence and underlying mechanisms, Food Biosci,
doi:10.1016/j.fbio.2021.100891Mehrbod, Abdalla, Fotouhi, Heidarzadeh, Aro et al., Immunomodulatory properties of quercetin-3-O-alpha-L-rhamnopyranoside from Rapanea melanophloeos against influenza a virus, BMC Complement Altern. Med,
doi:10.1186/s12906-018-2246-1Mora, Iwata, Von Andrian, Vitamin effects on the immune system: Vitamins A and D take centre stage, Nat. Rev. Immunol,
doi:10.1038/nri2378Moran-Santibanez, Pena-Hernandez, Cruz-Suarez, Ricque-Marie, Skouta et al., Virucidal and Synergistic Activity of Polyphenol-Rich Extracts of Seaweeds against Measles Virus, Viruses,
doi:10.3390/v10090465Mostafavi-Pour, Zal, Monabati, Vessal, Protective effects of a combination of quercetin and vitamin E against cyclosporine A-induced oxidative stress and hepatotoxicity in rats, Hepatol. Res,
doi:10.1111/j.1872-034X.2007.00273.xMunafo, Donati, Brindani, Ottonello, Armirotti et al., Quercetin and luteolin are single-digit micromolar inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase, Sci. Rep,
doi:10.1038/s41598-022-14664-2Nam, Sharma, Nguyen, Chakraborty, Sharma et al., Application of Bioactive Quercetin in Oncotherapy: From Nutrition to Nanomedicine, Molecules,
doi:10.3390/molecules21010108Nguyen, Woo, Kang, Nguyen, Kim et al., Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris, Biotechnol. Lett,
doi:10.1007/s10529-011-0845-8Niazvand, Orazizadeh, Khorsandi, Abbaspour, Mansouri et al., Effects of Quercetin-Loaded Nanoparticles on MCF-7 Human Breast Cancer Cells, Medicina,
doi:10.3390/medicina55040114Nishimuro, Ohnishi, Sato, Ohnishi-Kameyama, Matsunaga et al., Estimated daily intake and seasonal food sources of quercetin in Japan, Nutrients,
doi:10.3390/nu7042345Park, Yuk, Ryu, Lim, Kim et al., Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors, J. Enzyme. Inhib. Med. Chem,
doi:10.1080/14756366.2016.1265519Parkhomenko, Kozhukhov, Lutay, Multicenter randomized clinical trial of the efficacy and safety of intravenous quercetin in patients with ST-elevation acute myocardial infarction, Eur. Heart J,
doi:10.1093/eurheartj/ehy565.2152Pashevin, Tumanovska, Dosenko, Nagibin, Gurianova et al., Antiatherogenic effect of quercetin is mediated by proteasome inhibition in the aorta and circulating leukocytes, Pharmacol. Rep
Pawar, Pal, Molecular and functional resemblance of dexamethasone and quercetin: A paradigm worth exploring in dexamethasone-nonresponsive COVID-19 patients, Phytother. Res,
doi:10.1002/ptr.6886Peng, Vitamin C Infusion for the Treatment of Severe 2019-nCoV Infected Pneumonia
Prabu, Shagirtha, Renugadevi, Quercetin in combination with vitamins (C and E) improves oxidative stress and renal injury in cadmium intoxicated rats, Eur. Rev. Med. Pharmacol. Sci
Qiu, Kroeker, He, Kozak, Audet et al., Prophylactic Efficacy of Quercetin 3-β-O-d-Glucoside against Ebola Virus Infection, Antimicrob. Agents Chemother,
doi:10.1128/AAC.00307-16Riva, Ronchi, Petrangolini, Bosisio, Allegrini, Improved Oral Absorption of Quercetin from Quercetin Phytosome(R), a New Delivery System Based on Food Grade Lecithin, Eur. J. Drug Metab. Pharmacokinet
Rogerio, Dora, Andrade, Chaves, Silva et al., Anti-inflammatory effect of quercetin-loaded microemulsion in the airways allergic inflammatory model in mice, Pharmacol. Res,
doi:10.1016/j.phrs.2009.10.005Rondanelli, Perna, Gasparri, Petrangolini, Allegrini et al., Promising Effects of 3-Month Period of Quercetin Phytosome((R)) Supplementation in the Prevention of Symptomatic COVID-19 Disease in Healthcare Workers: A Pilot Study, Life,
doi:10.3390/life12010066Ryu, Jeong, Kim, Kim, Park et al., Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition, Bioorg. Med. Chem,
doi:10.1016/j.bmc.2010.09.035Sagar, Rathinavel, Lutz, Struble, Khurana et al., Bromelain Inhibits SARS-CoV-2 Infection in VeroE6 Cells, Biorxiv Prepr. Serv. Biol,
doi:10.1101/2020.09.16.297366Schwarz, Sauter, Wang, Zhang, Sun et al., Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus, Planta. Med,
doi:10.1055/s-0033-1360277Seremet, Dumitrescu, Radesi, Katona, Doagă et al., Photobiomodulation of quercetin antiproliferative effects seen in human acute T leukemic Jurkat cells, Rom. J. Biophys
Shrivastava, Shrivastava, Synergistic Compositions for the Treatment of Topical Viral Infections, U.S. Patent No
Shysh, Pashevin, Dosenko, Moibenko, Correction of lipid peroxidation and antioxidant system disorders by bioflavonoids during modeling of cholesterol atherosclerosis in rabbits, Fiziol. Zh,
doi:10.15407/fz57.02.019Siriwong, Teethaisong, Thumanu, Dunkhunthod, Eumkeb, The synergy and mode of action of quercetin plus amoxicillin against amoxicillin-resistant Staphylococcus epidermidis, BMC Pharmacol. Toxicol,
doi:10.1186/s40360-016-0083-8Stanek, Kafarski, Jasicka-Misiak, Development of a high performance thin layer chromatography method for the rapid qualification and quantification of phenolic compounds and abscisic acid in honeys, J. Chromatogr. A
Sternberg, Chadha, Lieberman, Hojnacki, Drake et al., Quercetin and interferon-β modulate immune response(s) in peripheral blood mononuclear cells isolated from multiple sclerosis patients, J. Neuroimmunol,
doi:10.1016/j.jneuroim.2008.09.008Tang, Deng, Zhou, Li, Ge et al., Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects, Biomed. Pharm,
doi:10.1016/j.biopha.2019.109604Tao, Yang, Shi, Xue, Yang et al., Complementary and alternative medicine is expected to make greater contribution in controlling the prevalence of influenza, Biosci. Trends,
doi:10.5582/bst.2013.v7.5.253Ubani, Agwom, Shehu, Luka, Umera et al., Molecular Docking Analysis of Some Phytochemicals on Two Sars-CoV-2 Targets, BioRxiv,
doi:10.1101/2020.03.31.017657Ul Qamar, Alqahtani, Alamri, Chen, Structural basis of SARS-CoV-2 3CL(pro) and anti-COVID-19 drug discovery from medicinal plants, J. Pharm. Anal,
doi:10.1016/j.jpha.2020.03.009Valentova, Sima, Rybkova, Krizan, Malachova et al., Anti)mutagenic and immunomodulatory properties of quercetin glycosides, J. Sci. Food Agric,
doi:10.1002/jsfa.7251Verna, Liso, Cavalcanti, Bianco, Di Sarno et al., Quercetin Administration Suppresses the Cytokine Storm in Myeloid and Plasmacytoid Dendritic Cells, Int. J. Mol. Sci,
doi:10.3390/ijms22158349Wang, Yao, Zhou, Yang, Chaudry et al., Bacteriostatic Effect of Quercetin as an Antibiotic Alternative In Vivo and Its Antibacterial Mechanism In Vitro, J. Food Prot,
doi:10.4315/0362-028X.JFP-17-214Warren, Paulhill, Davidson, Lupton, Taddeo et al., Quercetin may suppress rat aberrant crypt foci formation by suppressing inflammatory mediators that influence proliferation and apoptosis, J. Nutr,
doi:10.3945/jn.108.096271Wong, He, Siragam, Bi, Mbikay et al., Antiviral activity of quercetin-3-β-O-D-glucoside against Zika virus infection, Virol. Sin,
doi:10.1007/s12250-017-4057-9Worldmeters, COVID-19 Coronavirus Pandemic
Wu, Li, Li, He, Jiang et al., Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry, Viruses,
doi:10.3390/v8010006Xiao, Shi, Liu, Wang, Xie et al., Quercetin suppresses cyclooxygenase-2 expression and angiogenesis through inactivation of P300 signaling, PLoS ONE,
doi:10.1371/journal.pone.0022934Yahfoufi, Alsadi, Jambi, Matar, The Immunomodulatory and Anti-Inflammatory Role of Polyphenols, Nutrients,
doi:10.3390/nu10111618Yamshchikov, Desai, Blumberg, Ziegler, Tangpricha, Vitamin D for treatment and prevention of infectious diseases: A systematic review of randomized controlled trials, Endocr. Pract,
doi:10.4158/EP09101.ORRYang, Islam, Wang, Li, Chen, Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective, Int. J. Biol. Sci,
doi:10.7150/ijbs.45538Yang, Li, Liu, Zhen, Zhang et al., Chest CT Severity Score: An Imaging Tool for Assessing Severe COVID-19, Radiol. Cardiothorac. Imaging,
doi:10.1148/ryct.2020200047Yao, Xi, Hu, Gao, Cai et al., Inhibition of enterovirus 71 replication and viral 3C protease by quercetin, Virol. J,
doi:10.1186/s12985-018-1023-6Yu, Lee, Lee, Kim, Chin et al., Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13, Bioorg. Med. Chem. Lett,
doi:10.1016/j.bmcl.2012.04.081Zhang, Evaluation of anti-fatigue and immunomodulating effects of quercetin in strenuous exercise mice, IOP Conf. Ser. Earth Environ. Sci,
doi:10.1088/1755-1315/61/1/012046Zhang, Lin, Sun, Curth, Drosten et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors, Science
Zhang, Wu, Zhang, Deng, Peng, In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus, J. Integr. Med,
doi:10.1016/j.joim.2020.02.005Zheng, Deng, Liang, Chen, Guo et al., Antioxidant Activity of Quercetin and Its Glucosides from Propolis: A Theoretical Study, Sci. Rep,
doi:10.1038/s41598-017-08024-8Zhou, Hou, Shen, Huang, Martin et al., Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2, Cell Discov,
doi:10.1038/s41421-020-0153-3
