Potential of Natural Therapeutics Against SARS-CoV-2: Phenolic Compounds and Terpenes


  • Selahattin GÜRÜ

Received Date: 20.10.2021 Accepted Date: 30.11.2021 Nam Kem Med J 2022;10(2):119-128

Coronavirus disease-2019 caused by severe-coronavirus acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which emerged in China in late 2019 has created an unprecedented global health crisis affecting every sector of human life and causing great damage to the world economy. SARS-CoV- 2 is a viral respiratory tract virus that not only causes upper respiratory tract infection but also causes pneumonia and therefore mortality in some patients. There is currently no proven drug for the treatment of SARS-CoV-2. Many chemical and natural active compounds have been testing by the researchers for the treatment. These herbal-based antivirals have been the subject of many studies as they are less toxic and less likely to develop resistance by infectious microorganisms. It has been reported in many studies that natural therapeutics inhibit viral replication. In this review, phenolic compounds and terpenes, which are natural therapeutics known to have antiviral activity, have been evaluated for their potential in the treatment of SARS-CoV-2.

Keywords: Phenolic, terpene, secondary metabolite, SARS-CoV-2


Coronaviruses (CoV) are the family of viruses that caused severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and Middle East respiratory syndrome (MERS-CoV) outbreaks in recent years and came up with a new species of SARS-CoV-2, which was first detected in Wuhan, China at the end of 2019. CoV is an enveloped group of viruses that carry single-stranded ribonucleic acid (RNA) as genetic material in groups of viruses, capable of infecting humans and a wide variety of animal species. Viruses are simple organisms and consist of genetic material and a protein coat called capsid. Some virus species have an envelope consisting of phospholipids and glycoproteins outside the capsid. Viruses cannot reproduce or spread without invading a host cell. When the virus encounters host cells, typically epithelial cells in the nose, throat and lungs, it enters the cell by binding to receptors on the membrane of these cells. After it enters the cell, it opens its coating and begins to reproduce using the cell’s mechanisms. The spike (S) protein of SARS-CoV-2 is viral attachment to host angiotensin-converting enzyme 2 (ACE2) which is a receptor to get into the host cells. Transmembrane protease serine 2 (TMPRSS2) receptor is also crucial viral gateways in oral, lung, and intestinal epithelial cells of SARS-CoV-2 invasion1. 3-chymotrypsin- like protease (3CLpro), papain like protease (PLpro), RNA-dependent RNA polymerase, and S proteins must be major target of SARS-CoV-2 drugs2. SARS-CoV-2 has similar genomic sequence with SARS-CoV3. However, the rate of transmission and spread of SARS-CoV-2 infection is quite fast compared to other viral infections encountered so far4. SARS-CoV-2 binds to ACE2 receptor with a higher affinity in comparison to SARS-CoV5. Some vaccines are developed for SARS-CoV-2. The most prominent vaccine developers are Pfizer and BioNTech, Tüseb-Tübitak, Sanofi-GSK, SinoVac, AstraZeneca and the University of Oxford, Johnson  Johnson and Moderna. They use different strategies for vaccine development and delivery. The used types of vaccines are inactivated pathogen vaccines, subunit vaccines, deoxyribonucleic acid vaccines and mRNA (messenger RNA) vaccines and virus-like particle vaccines6. The Pfizer-BioNTech and Moderna vaccines consist of synthetically produced messenger RNAs (mRNAs) that encode a stabilized form of the S protein formulated in a lipid nanoparticle. In an interim analysis of the 2-dose regimen of the Pfizer-BioNTech coronavirus disease-2019 (COVID-19) vaccine, it was observed to provide 95% protection against symptomatic disease7. The studies also showed that Pfizer/BioNTech mRNA vaccine (BNT162b2) was effective in different types of variants8.

Symptoms of COVID-19 infection can be asymptomatic depending on the immune response of the host and comorbid diseases, as well as mild, moderate, severe or critical. In mild patients, there are no symptoms of pneumonia on imaging, and radiological findings of pneumonia, fever and respiratory symptoms are observed in moderate cases. In critical cases, respiratory failure (severe respiratory tract infection, acute respiratory distress syndrome), septic shock and/or multi-organ dysfunction/failure, myocarditis, arrhythmias, cardiogenic shock, metabolic acidosis, coagulation problems, endocrinopathies, acute kidney injury and hepatic dysfunction etc. are observed9,10. Reports also show that 30-60% of patients with COVID-19 suffer from neurological complications11. COVID-19 caused high anxiety level in people working different sectors12. In clinical practice, approximately 20% of COVID-19 patients have abnormal coagulation function and coagulation disorders occur in almost all critically ill patients13. Respiratory failure seen in the severe disease picture in COVID-19 is often in the form of hypoxemic respiratory failure. Advanced age, presence of comorbid diseases (cardiovascular disease, diabetes mellitus, chronic respiratory disease, hypertension, cancer), and male gender are risk factors for the development of severe disease14. The symptoms may differ depending on the immune responses of patients. It is extremely important to activate the immune response and combat viral infection by increasing the body’s combat mechanism, thereby controlling CoV infections15. If the virus infects the body, our strong immune system is one of the most effective methods of avoiding the effects of the infected virus. The immune system fulfills the function of defending the human body against disease-causing microorganisms. The best step you can take to keep your immune system strong and healthy naturally is choosing a healthy lifestyle. The immune system against diseases should be strengthened with food and other natural product supplements16,17.

Plants have been used in the treatment of various diseases since ancient times. According to World Health Organization, about 80% of the world’s population use medicinal herbs to meet their health needs18. Plants are able to synthesize diverse classes of chemical compounds, named secondary metabolites. The concept of secondary metabolites was first defined in 1891 by biochemist Albrecht Kossel, the Nobel Prize winner in physiology or medicine19. The chemical composition of the herbs provides a better understanding of the herb’s medicinal value. Secondary metabolites help plants adapt to environmental conditions, defend, protect, survive and regulate their relationships with the ecosystem. They protect the plant against herbivore; bacterial and fungal pathogen attacks and increases their competitiveness with other plants in the same environment. They also protect the plant against abiotic stress factors such as temperature changes, water, light, ultraviolet and mineral substances20. Though the functions of secondary products in the plant differ, those with cytotoxic effects against microbial pathogens are used as “antimicrobial agents” in medicine. It is neurotoxic on the central nervous system against herbivores and they are used as anti-depressants, sedatives, muscle relaxants or anesthetic drugs21. Some secondary plant metabolites have shown strong antiviral activity against various viral strains such as CoV, human immunodeficiency virus (HIV), influenza virus, SARS22-25. When discovering new drugs from both synthetic and natural sources, in silico virtual screening studies should be the first step then in vitro, in vivo and clinical studies should be carried out. It has been shown that plant secondary metabolites are probably one of the most significant drugs against SARS-CoV-2 by silico analysis26-30. The search for natural agents that inhibit different viruses is important to develop a plant-based drug for SARS-CoV-2. The aim of this study is to report previously researched secondary metabolites (phenolics, and terpenes/terpenoids of plants with antiviral properties that could potentially be used in SARS-CoV-2) and to contribute to the public health by antiviral natural therapeutics (Figure 1).


Phenolic compounds are secondary metabolites abundant in plants. There are various phenolic compounds in different qualities and amounts in all vegetables and fruits31. Plant phenolics are thought to play a key role as defense compounds in situations where environmental stresses may cause enhanced production of free radicals and other oxidative species in plants32. These compounds also play an important role in the human diet. They are important in terms of their antimicrobial and antioxidative effects and causing enzyme inhibition. Polyphenols comprise a wide range of polyhydroxylated compounds (phenolic acids, cinnamic acids, lignans, coumarins, flavonoids, tannins, among others) and for this reason is divided into classes and subclasses. Flavonoids are low molecular weight secondary metabolites in plants that have positive effects on human health. They are the most prevalent phenolic compounds in the human diet. Flavonoids fall into various classes and in general, six basic classes of flavonoids are reported. These are flavones, flavonones, flavonols, isoflavonoids, anthocyanins and proanthocyanidin. Flavonoids are in aglycon or glycoside structures. The predominant form of flavonoids in foods is the form of glycoside. Absorption of this form from the intestines is more difficult than the lean form. Flavonoid glycosides are separated from the sugar part before entering the intestine, and aglycones can pass freely through cell membranes33,34. Phenolic therapeutics are used for the treatment of various disease types35,36.


The interaction of phenols with the immune system has complex effects on the prevention of the disease, the treatment of the disease and the immune system. When free radicals are more than the antioxidant capacity of our body, oxidative damage occurs in our cells. Phenols reduce oxidative stress by scavenging free radicals and inflammatory prooxidants such as hydrogen peroxide37. There is a close relationship between inflammation and oxidative stress. Especially high free radical production by macrophages at the infection site causes oxidative stress. SARS-CoV or SARS-CoV-2-related complications are mostly caused by severe inflammation caused by viral replication. Patients in critical care units with severe COVID-19 had elevated plasma levels of various cytokines, including granulocyte-colony stimulating factor, interferon (IFN) gamma-induced protein 10, and macrophage inflammatory proteins38. Polyphenols support immunity against foreign pathogens in a variety of ways. Polyphenol receptors identify and facilitate cellular uptake of polyphenols, which subsequently activate signaling pathways to generate immunological responses in different immune cells. Polyphenols interact with the intestinal immune system, leading to both protective and deleterious reactions in the host. For example, resveratrol has the ability to improve human immunity and antioxidative systems. Resveratrol has been displayed to directly target central cell parts of adaptive immunity, like macrophages, large lymphocytes, and dendritic cells. In animal experiments, resveratrol showed an immunomodulatory effect by diminishing the expression of activating CD28 and CD80 receptors on immune cells and enhancing the production of the immunosuppressive cytokine IL-1039.


There are also many studies in the literature that show antiviral potential of phenolics. Natural polyphenol compounds such as quercetin40, myricetin41, apigenin42 and resveratrol43 have shown antiviral effect against CoVs. Theaflavin, a polyphenolic compound in black tea, have exhibited broad‐spectrum antiviral activity against different viruses such as influenza A and B viruses and hepatitis C virus (HCV)44,45. Theaflavin has also been shown to have potential inhibitory effect against SARS‐CoV‐2 that targets RNA‐dependent RNA polymerase (RdRp) which is a significant enzyme that catalyzes the replication of RNA from RNA templates46. Stilbenes have antiviral activity against HIV and HCV47,48. Flavonoids interfere for NLRP3 inflammasome-associated disorders49. SARS CoVs activate the NLRP3 inflammasome in lipopolysaccharide-primed macrophages and cause NLRP3 inflammasome activation50. Some flavonoids, such as luteolin51, myricetin50, apigenin52, quercetin53, kaempferol54, baicalin55 and wogonoside56 , inhibit NLRP3 inflammasome activation. Myricetin has been shown to act as a SARS-CoV inhibitor41. Isorhamnetin, apigenin, kaempferol, formononetin and penduletin show antiviral protective efficacy against enterovirus 71 (EV71) infection57. Apigenin has also been shown to be active against herpes simplex virus-1 (HSV-1), poliovirus type 2 and HCV58,59 Apigenin is also anti-adenoviruses and hepatitis B virus (HBV)60. Emodin was found to block the interaction of SARS CoV S protein and ACE2. Therefore, it may have therapeutic potential in the treatment of SARS CoVs61. Resveratrol has been shown to significantly prevent MERS-CoV infection62. Kaempferol, a flavonol, exhibits inhibitory effect against Murine Norovirus and Feline Calicivirus63. Kaempferol 3-O-α-L-rhamnopyranoside, extracted from Zanthoxylum piperitum, has been shown to have antiviral activity against Influenza A virus64. Studies have revealed that quercetin, a natural flavonoid, also display strong antiviral activity against a range of infections caused by HSV, Influenza, HBV, Murine Coronavirus and Dengue viruse in cell culture and mouse models65-67. In addition, quercetin was found to inhibit H1N1 and H7N9 viruses in silico analysis68,69. Quercetin, rosmarinic acid, and hesperitin have also shown good binding affinity with SARS-CoV-2 viral protein targets in silico virtual screening70. Due to caffeic acid, p-coumaric acid, kaempferol and mainly quercetin, which are the phenolic compounds detected with ethanol of Origanum vulgare, the plant shows an inhibitory effect against Alphaarterivirus equid which causes the equine viral arteritis (EVA) diseases71. A study has shown that baicalein, a flavonoid extracted from the roots of S. baicalensis, inhibits the activity of SARS-CoV-2 3CLpro in vitro. Baicalein has been shown to have anti-SARS-CoV-2 activity by molecular docking analysis72. Papyriflavonol A, a flavonol isolated from Broussonetia papyrifera, has potent SARS-CoV PLpro inhibitory activity73. Antiviral activity of the myricetin derivatives and methoxyflavones obtained from Marcetia taxifolia have been evaluated against HBV, HSV and Poliovirus. The methoxyflavones have shown antiviral effect against all the evaluated viruses without cytotoxic effects74. Phenolic acids have been reported to show antiviral activity against HSV-1 in a study75. Rutin is a very impressive therapeutic as anti-inflammatory and antiviral. Rutin has shown the highest activity as SARS-CoV-2 protease inhibitory in the molecular docking simulation study. Therefore, in vivo and docking studies of rutin can be hopeful for SARS-CoV-2 potential76,77. Luteolin has been found to have inhibitory activity against EV71, coxsackievirus A1 and SARS CoV78. The studies show that flavonoids and polyphenols have antiviral effects against many diseases and can be potentially used against SARS-CoV-2 (Table 1, Figure 2).


Terpenes are a group of compounds commonly found in the plants and are the largest group of secondary metabolites composed of five carbon isoprene subunits. Terpenes are simple hydrocarbons while terpenoids are modified category of terpenes82. Terpenes are the major components of essential oils in most herbs and flowers. Terpenoids are a class of modified terpenes with different functional groups. Terpenoids are classified into monoterpenes, diterpenes, sesterpenes, triterpenes and sesquiterpenos according to the units of isoprene. Terpenoids are used in the treatment of many diseases due to their biological activity83.


Terpenes have strong effects on the immune system. The effects of naturally occurring triterpenoid compounds such as glycyrrhizic acid, ursolic acid, oleanolic acid and nomilin were studied on the immune system using Balb/c mice84. It has been observed that intraperitoneal treatments with five doses of terpenoid compounds increase the total white blood cell count. The results demonstrated the immunomodulatory activity of the naturally occurring triterpenoids used in the study. Terpenes also show anti-inflammatory activities. In a study, rats were treated for 11 days with the standard drug sulfasalazine (500 mg/kg po), geraniol (250 mg/kg po), or a combination of the standard drug and geraniol85. It was observed that it significantly reduced the total antioxidant capacity and reduced high nitric oxide (NO) and lipid peroxide levels. In a study, D-limonene was orally administered to rats at a dose of 10 mg/kg86. According to the results of the study, D-limonene showed important anti-inflammatory effects in vivo and in vitro, and its effects included protection at the epithelial barrier and reduction of cytokines. Nuclear transcription factor-kappa B plays an important role in the regulation of immune and inflammatory responses. Labdane diterpenoids show anti-inflammatory effect by inhibiting NF-κB87. Tanshinones, a class of abietane diterpene, can reduce inflammation and increase immune responses88. Experimental studies have shown that terpenes are able to decrease pro-inflammatory cytokines [tumor necrosis factor (TNF)-α and β, IL-1, IL-1β, IL-6, IL-17, IFN-γ] and enhance anti-inflammatory cytokines (IL-4, IL-10, TGF-β1)89. Emodinol, a triterpene, decreases the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the serum of monosodium urate crystal-treated mice and provides a reduction in anti-gouty arthritis activity by improving inflammatory response90. In another study, glycyrrhizin (a kind of triterpenoid) was found to provide SARS-CoV-2 inhibition by down-regulating proinflammatory cytokines and preventing the formation of intracellular reactive oxygen species91.


There are many studies showing the antiviral properties of terpenes. Glycyrrhizin has shown antiviral effect against SARS, HBV and HIV92-94. It also has potential to inhibit SARS CoV-2. Glycyrrhizin has been shown to bind S-RBD and SARS-CoV-2 S-protein attachment with H-ACE2 receptor95. 1,8-Cineole, a terpene oxide, has been shown to interfere with the binding between RNA and infectious bronchitis virus (IBV) N-protein. So, it exhibits that 1,8-Cineole has anti-IBV properties96. (-)-α-pinene and (-)-β-pinene, which are the kinds of terpenoid, have also been shown to possess anti-IBV properties97. Triterpenoid saponins are active components isolated from Bupleurum falcatum, including saikosaponin A, B, C, and D. Saikosaponin B2 has been found to effectively inhibit HCV by neutralizing virus particles and preventing viral binding98. Saikosaponin B2 also has exhibited significant inhibition effect against human coronavirus 229E infection and it has been found that it has potent anticoronaviral activity99. Saikosaponin D has been found to have the ability to strongly inhibit EV-71100. Terpenoids may interfere with essential amino acid in the enzymatic cavity for inhibiting viral protease enzyme. Some terponoids, including thymoquinone, salvinorin A, bilobalide, citral, menthol, ginkgolide A, noscapine, forscolin, and beta selinene, have been shown to have inhibitory effect against COVID-19 protease molecular insertion by molecular docking method101. Isoborneol, an oxygenated monoterpene, has been shown to have a potent antiviral effect against HSV-1 and exactly inhibited glycosylation of viral proteins102. A study has shown that limonene, a cyclic monoterpene, is effective in reducing the epithelial expression of ACE2. It has also potential to reduce the mRNA levels of TMPRSS2103. Terpenes from Marrubium vulgare have been found to interfere with the replication of the HSV-1 and show antiviral effect against HSV-1104. Putranjivain A, a diterpen obtained from Euphorbia jolkini, has been shown to have an antiviral effect against HSV-2105. Moronic acid, extracted from the Rhus javanica, has potential to inhibit HSV-1106. Andrographolide, a diterpenoid lactone, has been shown to inhibit the replication process of the CKV107. Betulinic acid and platanic acid, which are the pentacyclic triterpenoid compounds isolated from Syzigium claviforum, have been found to inhibit HIV108. Oleanolic acid, a pentacyclic triterpenoid, have also shown anti-HIV activity (Table 2, Figure 3)109.


There are only a few clinical trials regarding the application of phenolic compounds and terpenes in SARS-CoV-2. A clinical trial covers the administration of zinc and resveratrol (a stilbene, a type of natural phenol) or double placebo for a period of 5 days in 60 ambulatory SARS-CoV-2 positive volunteers (range of 18-75 age) and monitoring for a 14-day period117. The aim of this study is to minimize viral load and severity of resulting COVID-19 disease. Combination therapy contains 50 mg of zinc picolinate for five days and 2 mg of Resveratrol for five days. The stage of this study is still phase 2. Another clinical trial has been conducted with the use of Epigallocatechin-3-gallate, a phenol found in green and black tea plants, in 524 volunteer healthcare worker participants118. The total dose of EGCG per patient was 750 mg per day, 3 capsules per day for 40 days. Participants also took the same dose of starch as a placebo. The purpose of this clinical trial was to determine the efficacy of Previfenon® (EGCG) in preventing COVID-19, enhancing systemic immunity, and reducing the frequency and intensity of selected symptoms when used as pre-exposure chemoprophylaxis to SARS-CoV-2. The stage of this study is still phase 2. Combination of curcumin (a terpene), quercetin (a flavonoid) and vitamin D is used in an ongoing clinical trial in phase 2 to investigate for early COVID-19 symptoms improvement and viral clearance in outpatients119. There are 100 participants who are 18 years old and older, tested positive for SARS-CoV-2 by RT-PCR and exhibit typical symptoms of COVID-19 disease. Soft capsule of the investigational treatment contains 42 mg curcumin, 65 mg quercetin and 90 units Vitamin D. Four capsules per day for 14 days are taken. Quercetin (flavonoid) is administrated on 80 participants in a clinical trial to investigate the effectiveness of phytotherapy in the treatment of SARS-CoV-2120. Participants will receive one tablet times three per day from quercetix and placebo groups. This study is still phase 1. Combination therapy of quercetin, bromelain, zinc and vitamin C on the clinical outcomes of patients infected with COVID-19 was studied on 60 participants121. A daily dose of drugs included quercetin (500 mg), bromelain (500 mg), zinc (50 mg), vitamin C (1000 mg) by proven COVID-19 cases intervention. The stage of this clinic trial is phase 4.

The biggest problem with the use of natural products in the treatment of diseases is their low solubility and bioavailability, which causes problems in clinical studies. Bioavailability issues can be evaluated before starting high-budget clinical trials. The ways to improve drug delivery, bio distribution, biodegradability and bioavailability of plant-based secondary metabolites such as phenolic compounds and terpenes should be sought. Nano carrier systems can be useful as a solution for these problems. Natural therapeutics administered regularly in low doses can reduce the entry of the virus into cells and thus stop the progression of the infection.


The whole world faced a major health crisis with the SARS-CoV-2 pandemic, which caused many human deaths and adversely affected many industries. The fact that it is so widespread and fatal raises the need for improvement of treatment as soon as possible. However, the reliable and certified drug has not yet been developed for the SARS-CoV-2. The use of natural therapeutics has begun with the history of humanity and a significant number of effective plants derived drugs have been developed. They are effective in enhancing the immune response of the host against viral pathogens; therefore, it is considered as a protective and complementary treatment opportunity. Secondary metabolites of plants such as phenolic compounds and terpenes could be highly promising complementary therapeutic agents for the disease. The studies show that secondary metabolites exhibit antiviral activity against different viruses so they can be highly promising therapeutics for the SARS-CoV-2. Natural therapeutics must be subjected to in vitro and experimental trials to determine safe and therapeutic levels before conducting clinical trials in humans. This study reveals the antiviral properties of some natural therapeutics for new drug development to overcome these and future pandemic situations. It is thought that the information provided in this study will be useful in the process of developing safe, effective anti-CoV therapeutic agents from compounds derived from natural products.


Peer-review: Externally peer-reviewed.

Authorship Contributions

Concept -  Design - Data Collection or Processing - Analysis or Interpretation - Literature Search - Writing: D.Y.A., S.G.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

  1. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181:271-80.e8.
  2. Wu C, Liu Y, Yang Y, Zhang P, Zhong W, Wang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B. 2020;10:766-88.
  3. Khanal LN, Pokharel YR, Sharma K, Kalauni SK. Plant-Derived secondary metabolites as potential mediators against COVID-19: A review. PAJ, “COVID-19 & Beyond”. 2020;3:1-18.
  4. Kırbaş İ, Sözen A, Tuncer AD, Kazancıoğlu FŞ. Comparative analysis and forecasting of COVID-19 cases in various European countries with ARIMA, NARNN and LSTM approaches. Chaos Solitons Fractals. 2020;138:110015.
  5. Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020;581:221-4.
  6. Kyriakidis NC, López-Cortés A, González EV, Grimaldos AB, Prado EO. SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. NPJ Vaccines. 2021;6:28.
  7. Connors M, Graham BS, Lane HC, Fauci AS. SARS-CoV-2 Vaccines: Much Accomplished, Much to Learn. Ann Intern Med. 2021;174:687-90.
  8. Bian L, Gao F, Zhang J, He Q, Mao Q, Xu M, et al. Effects of SARS-CoV-2 variants on vaccine efficacy and response strategies. Expert Rev Vaccines. 2021;20:365-73.
  9. Shang Y, Pan C, Yang X, Zhong M, Shang X, Wu Z, et al. Management of critically ill patients with COVID-19 in ICU: statement from front-line intensive care experts in Wuhan, China. Ann Intensive Care. 2020;10:73.
  10. Varatharaj A, Thomas N, Ellul MA, Davies NWS, Pollak TA, Tenorio EL, et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry. 2020;7:875-82.
  11. Prasad K, AlOmar SY, Alqahtani SAM, Malik MZ, Kumar V. Brain Disease Network Analysis to Elucidate the Neurological Manifestations of COVID-19. Mol Neurobiol. 2021;58:1875-93.
  12. Cevher C, Altunkaynak B, Gürü M. Impacts of COVID-19 on Agricultural Production Branches: An Investigation of Anxiety Disorders among Farmers. Sustainability. 2021;13:5186.
  13. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.
  14. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323:1239-42.
  15. Aydın DY, Gürü M, Gürü S. Effect of Alkaloids on SARS-CoV-2. Naturengs Covid-19 Special Issue. 2020:10-8.
  16. High KP. Nutritional strategies to boost immunity and prevent infection in elderly individuals. Clin Infect Dis. 2001;33:1892-900.
  17. Simpson RJ, Kunz H, Agha N, Graff R. Exercise and the Regulation of Immune Functions. Prog Mol Biol Transl Sci. 2015;135:355-80.
  18. WHO Global Report on Traditional and Complementary Medicine 2019. World Health Organization;2019.
  19. Hartmann T. The lost origin of chemical ecology in the late 19th century. Proc Natl Acad Sci U S A. 2008;105:4541-46.
  20. Yang L, Wen KS, Ruan X, Zhao YX, Wei F, Wang Q. Response of Plant Secondary Metabolites to Environmental Factors. Molecules. 2018;23:762.
  21. Rungsung W, Ratha KK, Dutta S, Dixit AK, Hazra J. Secondary Metabolites of plants in drugs discovery. W J Phar Res. 2015;4:604-13.
  22. Kim DW, Seo KH, Curtis-Long MJ, Oh KY, Oh JW, Cho JK, et al. Phenolic phytochemical displaying SARS-CoV papain-like protease inhibition from the seeds of Psoralea corylifolia, J Enzyme Inhib Med Chem. 2014;29:59-63.
  23. Reichling J, Neuner A, Sharaf M, Harkenthal M, Schnitzler P. Antiviral activity of Rhus aromatica (fragrant sumac) extract against two types of herpes simplex viruses in cell culture. Pharmazie. 2009;64:538-41.
  24. Zhou B, Yang Z, Feng Q, Liang X, Li J, Zanin M, et al. Aurantiamide acetate from baphicacanthus cusia root exhibits anti-inflammatory and anti-viral effects via inhibition of the NF-B signaling pathway in Influenza A virus-infected cells. J Ethnopharmacol. 2017;199:60-7.
  25. Park JY, Ko JA, Kim DW, Kim YM, Kwon HJ, Jeong HJ, et al. Chalcones isolated from Angelica keiskei inhibit cysteine proteases of SARS-CoV. J Enzyme Inhib Med Chem. 2016;31:23-30.
  26. Subbaiyan A, Ravichandran K, Singh SV, Sankar M, Thomas P, Dhama K, et al. In silico molecular docking analysis targeting SARS-CoV-2 spike protein and selected herbal constituents. J Pure Appl Microbiol. 2020;14(Suppl 1):989-98.
  27. Nivetha R, Bhuvaragavan S, Muthu Kumar T, Ramanathan K, Janarthanan S. Inhibition of multiple SARS-CoV-2 proteins by an antiviral biomolecule, seselin from Aegle marmelos deciphered using molecular docking analysis. J Biomol Struct Dyn. 2021:1-12.
  28. Basu A, Sarkar A, Maulik U. Computational approach for the design of potential spike protein binding natural compounds in SARS- CoV-2. Res. Sq. 2020;1-22.
  29. Krishnasamy R, Anand T, Baba M, Bharath MV, Phuntsho J, Arunachalam D, et al. In silico analysis of active compounds from siddha herbal infusion of Ammaiyar Koondhal Kudineer (Akk) against SARS-CoV- 2 spike protein and its ACE2 receptor complex. SSRN Online J. 2020;1-47. Preprint
  30. Naik SR, Bharadwaj P, Dingelstad N, Kalyaanamoorthy S, Mandal SC, Ganesan A, et al. Structure-based virtual screening, molecular dynamics and binding affinity calculations of some potential phytocompounds against SARS-CoV-2. J Biomol Struct Dyn. 2021:1-18.
  31. Agati G, Azzarello E, Pollastri S, Tattini M. Flavonoids as antioxidants in plants: location and functional significance. Plant Sci. 2012;196:67-76.
  32. Lattanzio V, Phenolic Compounds: Introduction. In: Ramawat K., Mérillon JM. (eds) Natural Products. Berlin, Heidelberg: Springer; 2013.
  33. De Pascual-Teresa S, Sanchez-Moreno C, Granado F, Olmedilla B, De Ancos B, Cano M.P. Short and mid-term bioavailability of flavanones from oranges in humans. Curr Top Nutraceut R. 2007;5:129-34.
  34. Viskupicova J, Ondrejovic M, Sturdik E. Bioavailability and metabolism of flavonoids. J Food Nutr Res. 2008;47:151-62.
  35. Cassidy L, Fernandez F, Johnson JB, Naiker M, Owoola AG, Broszczak DA. Oxidative stress in alzheimer’s disease: A review on emergent natural polyphenolic therapeutics. Complement Ther Med. 2020;49:102294.
  36. Khan H, Sureda A, Belwal T, Çetinkaya S, Süntar İ, Tejada S, et al. Polyphenols in the treatment of autoimmune diseases. Autoimmun Rev. 2019;18:647-57.
  37. Tekin İÖ, Marotta F. Polyphenols and Immune System. Ronald Ross Watson, Victor R. Preedy, Sherma Zibadi (eds.) Polyphenols: Prevention and Treatment of Human Disease. Academic Press. 2018;263-76.
  38. Iddir M, Brito A, Dingeo G, Fernandez Del Campo SS, Samouda H, La Frano MR, et al. Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients. 2020;12:1562.
  39. Ding S, Jiang H, Fang J. Regulation of Immune Function by Polyphenols. J Immunol Res. 2018;2018:1264074.
  40. Chiow KH, Phoon MC, Putti T, Tan BK, Chow VT. 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. 2016;9:1-7.
  41. Yu MS, Lee J, Lee JM, Kim Y, Chin YW, Jee JG, et al. Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorg Med Chem Lett. 2012;22:4049-54.
  42. Ryu YB, Jeong HJ, Kim JH, Kim YM, Park JY, Kim D, et al. Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition. Bioorg Med Chem. 2010;18:7940-7.
  43. Wahedi HM, Ahmad S, Abbasi SW. Stilbene-based natural compounds as promising drug candidates against COVID-19. J Biomol Struct Dyn. 2021;39:3225-34.
  44. Yang ZF, Bai LP, Huang WB, Li XZ, Zhao SS, Zhong NS, et al. Comparison of in vitro antiviral activity of tea polyphenols against influenza A and B viruses and structure-activity relationship analysis. Fitoterapia. 2014;93:47-53.
  45. Chowdhury P, Sahuc ME, Rouillé Y, Rivière C, Bonneau N, Vandeputte A, et al. Theaflavins, polyphenols of black tea, inhibit entry of hepatitis C virus in cell culture. PLoS One. 2018;13:e0198226.
  46. Lung J, Lin YS, Yang YH, Chou YL, Shu LH, Cheng YC, et al. The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase. J Med Virol. 2020;92:693-7.
  47. Gastaminza P, Pitram SM, Dreux M, Krasnova LB, Whitten-Bauer C, Dong J, et al. Antiviral stilbene 1,2-diamines prevent initiation of hepatitis C virus RNA replication at the outset of infection. J Virol. 2011;85:5513-23.
  48. Krawczyk H. The stilbene derivatives, nucleosides, and nucleosides modified by stilbene derivatives. Bioorg Chem. 2019;90:103073.
  49. Zhang X, Xu A, Lv J, Zhang Q, Ran Y, Wei C, et al. Development of small molecule inhibitors targeting NLRP3 inflammasome pathway for inflammatory diseases. Eur J Med Chem. 2020;185:111822.
  50. Chen IY, Moriyama M, Chang MF, Ichinohe T. Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Front Microbiol. 2019;10:50.
  51. Zhang G, Zhang B, Zhang X, Bing F. Homonojirimycin, an alkaloid from dayflower inhibits the growth of influenza A virus in vitro. Acta Virol. 2013;57:85-6.
  52. Yamagata K, Hashiguchi K, Yamamoto H, Tagami M. Dietary Apigenin Reduces Induction of LOX-1 and NLRP3 Expression, Leukocyte Adhesion, and Acetylated Low-Density Lipoprotein Uptake in Human Endothelial Cells Exposed to Trimethylamine-N-Oxide. J Cardiovasc Pharmacol. 2019;74:558-65.
  53. Choe JY, Kim SK. Quercetin and Ascorbic Acid Suppress Fructose-Induced NLRP3 Inflammasome Activation by Blocking Intracellular Shuttling of TXNIP in Human Macrophage Cell Lines. Inflammation. 2017;40:980-94.
  54. Lim H, Min DS, Park H, Kim HP. Flavonoids interfere with NLRP3 inflammasome activation. Toxicol Appl Pharmacol. 2018;355:93-102.
  55. Fu S, Xu L, Li S, Qiu Y, Liu Y, Wu Z, et al. Baicalin suppresses NLRP3 inflammasome and nuclear factor-kappa B (NF-B) signaling during Haemophilus parasuis infection. Vet Res. 2016;47:80.
  56. Sun Y, Zhao Y, Yao J, Zhao L, Wu Z, Wang Y, et al. Wogonoside protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-B and NLRP3 inflammasome activation. Biochem Pharmacol. 2015;94:142-54.
  57. Dai W, Bi J, Li F, Wang S, Huang X, Meng X, et al. Antiviral Efficacy of Flavonoids against Enterovirus 71 Infection in Vitro and in Newborn Mice. Viruses. 2019;11:625.
  58. Manvar D, Mishra M, Kumar S, Pandey VN. Identification and evaluation of anti hepatitis C virus phytochemicals from Eclipta alba. J Ethnopharmacol. 2012;144:545-54.
  59. Visintini Jaime MF, Redko F, Muschietti LV, Campos RH, Martino VS, Cavallaro LV. In vitro antiviral activity of plant extracts from Asteraceae medicinal plants. Virol J. 2013;10:245.
  60. Chiang LC, Ng LT, Cheng PW, Chiang W, Lin CC. Antiviral activities of extracts and selected pure constituents of Ocimum basilicum. Clin Exp Pharmacol Physiol. 2005;32:811-6.
  61. Ho TY, Wu SL, Chen JC, Li CC, Hsiang CY. Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Res. 2007;74:92-101.
  62. Lin SC, Ho CT, Chuo WH, Li S, Wang TT, Lin CC. Effective inhibition of MERS-CoV infection by resveratrol. BMC Infect Dis. 2017;17:144.
  63. Seo DJ, Jeon SB, Oh H, Lee B-H, Lee S-Y, Oh SH, et al. Comparison of the antiviral activity of flavonoids against murine norovirus and feline calicivirus. Food Control. 2016;60:25-30.
  64. Ha SY, Youn H, Song CS, Kang SC, Bae JJ, Kim HT, et al. Antiviral effect of flavonol glycosides isolated from the leaf of Zanthoxylum piperitum on influenza virus. J Microbiol. 2014;52:340-4.
  65. Lee S, Lee HH, Shin YS, Kang H, Cho H. The anti-HSV-1 effect of quercetin is dependent on the suppression of TLR-3 in Raw 264.7 cells. Arch Pharm Res. 2017;40:623-30.
  66. Wu W, Li R, Li X, He J, Jiang S, Liu S, et al. Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry. Viruses. 2015;8:6.
  67. Cheng Z, Sun G, Guo W, Huang Y, Sun W, Zhao F, et al. Inhibition of hepatitis B virus replication by quercetin in human hepatoma cell lines. Virol Sin. 2015;30:261-8.
  68. Liu Z, Zhao J, Li W, Shen L, Huang S, Tang J, et al. Computational screen and experimental validation of anti-influenza effects of quercetin and chlorogenic acid from traditional Chinese medicine. Sci Rep. 2016;6:19095.
  69. Liu Z, Zhao J, Li W, Wang X, Xu J, Xie J, et al. Molecular docking of potential inhibitors for influenza H7N9. Comput Math Methods Med. 2015;2015:480764.
  70. Rathinavel T, Meganathan B, Kumarasamy S, Ammashi S, Thangaswamy S, Ragunathan Y, et al. Potential COVID-19 drug from natural phenolic compounds through in silico virtual screening approach. Biointerface Res Appl Chem. 2021;11:10161-73.
  71. Blank DE, Corrêa RA, Freitag RA, Cleff MB, Hübner SO. Anti-equine arteritis virus activity of ethanolic extract and compounds from Origanum vulgare. HübnerSemina: Ciências Agrárias, Londrina. 2017;38:759-64.
  72. Liu H, Ye F, Sun Q, Liang H, Li C, Li S, et al. Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro. J Enzyme Inhib Med Chem. 2021;36:497-503.
  73. Park JY, Yuk HJ, Ryu HW, Lim SH, Kim KS, Park KH, et al. Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors. J Enzyme Inhib Med Chem. 2017;32:504-15.
  74. Ortega JT, Serrano ML, Suárez AI, Baptista J, Pujol FH, Cavallaro LV, et al. Antiviral activity of flavonoids present in aerial parts of Marcetia taxifolia against Hepatitis B virus, Poliovirus, and Herpes Simplex Virus in vitro. EXCLI J. 2019;18:1037-48.
  75. Medini F, Megdiche W, Mshvildadze V, Pichette A, Legault J, St-Gelais A, et al. Antiviral-guided fractionation and isolation of phenolic compounds from Limonium densiflorum hydroalcoholic extract. CR CHIM. 2016;19:726-32.
  76. Abd El-Mordy FM, El-Hamouly MM, Ibrahim MT, El-Rheem GA, Aly OM, Abd El-Kader AM, et al. Inhibition of SARS-CoV-2 main protease by phenolic compounds from Manilkara hexandra (Roxb.) Dubard assisted by metabolite profiling and in silico virtual screening. RSC Adv. 2020;10:32148-55.
  77. Hassan HA, Abdelmohsen UR, Aly OM, Desoukey SY, Mohamed KM, Kamel MS. Potential of Ficus microcarpa metabolites against SARS-CoV-2 main protease supported by docking studies. Nat Prod Res. 2022;36:994-8.
  78. Yi L, Li Z, Yuan K, Qu X, Chen J, Wang G, et al. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol. 2004;78:11334-9.
  79. Pandey P, Rane JS, Chatterjee A, Kumar A, Khan R, Prakash A, et al. Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development. J Biomol Struct Dyn. 2021;39:6306-16.
  80. Liu X, Raghuvanshi R, Ceylan FD, Bolling BW. Quercetin and Its Metabolites Inhibit Recombinant Human Angiotensin-Converting Enzyme 2 (ACE2) Activity. J Agric Food Chem. 2020;68:13982-9.
  81. Horne JR, Vohl MC. Biological plausibility for interactions between dietary fat, resveratrol, ACE2, and SARS-CoV illness severity. Am J Physiol Endocrinol Metab. 2020;318:E830-3.
  82. Perveen S, Al-Taweel A. Introductory chapter: Terpenes and terpenoids. In terpenes and terpenoids; IntechOpen: London, UK, 2018.
  83. Muhseen ZT, Li G. Promising Terpenes as Natural Antagonists of Cancer: An In-Silico Approach. Molecules. 2019;25:155.
  84. Raphael TJ, Kuttan G. Effect of naturally occurring triterpenoids glycyrrhizic acid, ursolic acid, oleanolic acid and nomilin on the immune system. Phytomedicine. 2003;10:483-9.
  85. Soubh AA, Abdallah DM, El-Abhar HS. Geraniol ameliorates TNBS-induced colitis: Involvement of Wnt/-catenin, p38MAPK, NFB, and PPAR signaling pathways. Life Sci. 2015;136:142-50.
  86. d’Alessio PA, Ostan R, Bisson JF, Schulzke JD, Ursini MV, Béné MC. Oral administration of d-limonene controls inflammation in rat colitis and displays anti-inflammatory properties as diet supplementation in humans. Life Sci. 2013;92:1151-6.
  87. de las Heras B, Hortelano S. Molecular basis of the anti-inflammatory effects of terpenoids. Inflamm Allergy Drug Targets. 2009;8:28-39.
  88. Zhang Y, Jiang P, Ye M, Kim SH, Jiang C, Lü J. Tanshinones: sources, pharmacokinetics and anti-cancer activities. Int J Mol Sci. 2012;13:13621-66.
  89. Carvalho AMS, Heimfarth L, Santos KA, Guimarães AG, Picot L, Almeida JGRS, et. al. Terpenes as possible drugs for the mitigation of arthritic symptoms – A systematic review, Phytomedicine. 2019;57:137-47.
  90. Chen L, Lan Z, Ma S, Zhao L, Yang X. Attenuation of gouty arthritis by emodinol in monosodium urate crystal-treated mice. Planta Med. 2013;79:634-8.
  91. Luo P, Liu D, Li J. Pharmacological perspective: glycyrrhizin may be an efficacious therapeutic agent for COVID-19. Int J Antimicrob Agents. 2020;55:105995.
  92. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361:2045-6.
  93. Sato H, Goto W, Yamamura J, Kurokawa M, Kageyama S, Takahara T, et al. Therapeutic basis of glycyrrhizin on chronic hepatitis B. Antiviral Res. 1996;30:171-7.
  94. Ito M, Sato A, Hirabayashi K, Tanabe F, Shigeta S, Baba M, et al. Mechanism of inhibitory effect of glycyrrhizin on replication of human immunodeficiency virus (HIV). Antiviral Res. 1988;10:289-98.
  95. Muhseen ZT, Hameed AR, Al-Hasani HMH, Tahir Ul Qamar M, Li G. Promising terpenes as SARS-CoV-2 spike receptor-binding domain (RBD) attachment inhibitors to the human ACE2 receptor: Integrated computational approach. J Mol Liq. 2020;320:114493.
  96. Yang Z, Wu N, Fu Y, Yang G, Wang W, Zu Y, et al. Anti-infectious bronchitis virus (IBV) activity of 1,8-cineole: effect on nucleocapsid (N) protein. J Biomol Struct Dyn. 2010;28:323-30.
  97. Yang Z, Wu N, Zu Y, Fu Y. Comparative anti-infectious bronchitis virus (IBV) activity of (-)-pinene: effect on nucleocapsid (N) protein. Molecules. 2011;16:1044-54.
  98. Lin LT, Chung CY, Hsu WC, Chang SP, Hung TC, Shields J, et al. Saikosaponin b2 is a naturally occurring terpenoid that efficiently inhibits hepatitis C virus entry. J Hepatol. 2015;62:541-8.
  99. Cheng PW, Ng LT, Chiang LC, Lin CC. Antiviral effects of saikosaponins on human coronavirus 229E in vitro. Clin Exp Pharmacol Physiol. 2006;33:612-6.
  100. Li C, Huang L, Sun W. Chen Y, He ML, Yue J, et al. Saikosaponin D suppresses enterovirus A71 infection by inhibiting autophagy. Sig Transduct Target Ther. 2019;4:4.
  101. Shaghaghi N. Molecular Docking Study of Novel COVID-19 Protease with Low Risk Terpenoides Compounds of Plants. ChemRxiv. Preprint. 2020.
  102. Armaka M, Papanikolaou E, Sivropoulou A, Arsenakis M. Antiviral properties of isoborneol, a potent inhibitor of herpes simplex virus type 1. Antiviral Res. 1999;43:79-92.
  103. Senthil Kumar KJ, Gokila Vani M, Wang CS, Chen CC, Chen YC, Lu LP, et al. Geranium and Lemon Essential Oils and Their Active Compounds Downregulate Angiotensin-Converting Enzyme 2 (ACE2), a SARS-CoV-2 Spike Receptor-Binding Domain, in Epithelial Cells. Plants (Basel). 2020;9:770.
  104. Fayyad AG, Ibrahim N, Yaakob WA. Phytochemical screening and antiviral activity of Marrubium vulgare. Malays J Microbiol. 2014;10:106-11.
  105. Cheng HY, Lin TC, Yang CM, Wang KC, Lin LT, Lin CC. Putranjivain A from Euphorbia jolkini inhibits both virus entry and late stage replication of herpes simplex virus type 2 in vitro. J Antimicrob Chemother. 2004;53:577-83.
  106. Kurokawa M, Basnet P, Ohsugi M, Hozumi T, Kadota S, Namba T, et al. Anti-herpes simplex virus activity of moronic acid purified from Rhus javanica in vitro and in vivo. J Pharmacol Exp Ther. 1999;289:72-8.
  107. Wintachai P, Kaur P, Lee RC, Ramphan S, Kuadkitkan A, Wikan N, et al. Activity of andrographolide against chikungunya virus infection. Sci Rep. 2015;5:14179.
  108. Fujioka T, Kashiwada Y, Kilkuskie RE, Cosentino LM, Ballas LM, Jiang JB, et al. Anti-AIDS agents, 11. Betulinic acid and platanic acid as anti-HIV principles from Syzigium claviflorum, and the anti-HIV activity of structurally related triterpenoids. J Nat Prod. 1994;57:243-7.
  109. Zhu YM, Shen JK, Wang HK, Cosentino LM, Lee KH. Synthesis and anti-HIV activity of oleanolic acid derivatives. Bioorg Med Chem Lett. 2001;11:3115-8.
  110. Park JY, Kim JH, Kim YM, Jeong HJ, Kim DW, Park KH, et al. Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases. Bioorg Med Chem. 2012;20:5928-35.
  111. Diniz LRL, Perez-Castillo Y, Elshabrawy HA, Filho CDSMB, de Sousa DP. Bioactive Terpenes and Their Derivatives as Potential SARS-CoV-2 Proteases Inhibitors from Molecular Modeling Studies. Biomolecules. 2021;11:74.
  112. Quy PT, My TTA, Bui TQ, Loan HTP, Van Anh T, Triet NT, et al. Molecular docking prediction of carvone and trans-geraniol inhibitability towards SARS-CoV-2. VJCH. 2021;59:457-66.
  113. Chiang LC, Ng LT, Liu LT, Shieh DE, Lin CC. Cytotoxicity and anti-hepatitis B virus activities of saikosaponins from Bupleurum species. Planta Med. 2003;69:705-9.
  114. Yao D, Li H, Gou Y, Zhang H, Vlessidis AG, Zhou H, et al. Betulinic acid-mediated inhibitory effect on hepatitis B virus by suppression of manganese superoxide dismutase expression. FEBS J. 2009;276:2599-614.
  115. Ryu YB, Park SJ, Kim YM, Lee JY, Seo WD, Chang JS, et al. SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii. Bioorg Med Chem Lett. 2010;20:1873-6.
  116. Tseng CK, Hsu SP, Lin CK, Wu YH, Lee JC, Young KC. Celastrol inhibits hepatitis C virus replication by upregulating heme oxygenase-1 via the JNK MAPK/Nrf2 pathway in human hepatoma cells. Antiviral Res. 2017;146:191-200.
  117. Hank K. Can SARS-CoV-2 viral load and COVID-19 disease severity be reduced by resveratrol-assisted zinc therapy (reszinate). 2020. Identifier NCT04542993. Available from:
  118. Elard K. Previfenon® as Chemoprophylaxis of COVID-19 in Health Workers (HERD). 2020. Identifier NCT04446065. Available from:
  119. Ayub Teaching Hospital. Dietary Supplements Vit D, Quercetin and Curcumin Combination for Early Symptoms of COVID-19. 2021. Identifier NCT05008003. Available from:
  120. Hôpital Universitaire Sahloul. The Effectiveness of Phytotherapy in SARS-COV2(COVID-19) (Quercetix). 2021. Identifier NCT04851821. Available from:
  121. Khalil AAK. The Study of Quadruple Therapy Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected With COVID-19. 2020. Identifier NCT04468139. Available from: