The pharmacological mechanism of quercetin as adjuvant therapy of COVID-19

Rizky et al., Life Research, doi:10.53388/life2022-0205-302, May 2022

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Quercetin for COVID-19

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Review of the pharmacological mechanism of quercetin as adjuvant therapy for COVID-19. Authors discuss how quercetin and its metabolites can inhibit SARS-CoV-2 entry and replication through various mechanisms, including interfering with the spike protein's interaction with ACE2 receptors, altering the tertiary structure of the main protease 3CL^pro, and binding to the RNA-dependent RNA polymerase. In Silico studies suggest quercetin is a promising candidate for halting viral entry and replication. Authors report that recent clinical trials support the use of quercetin, particularly in phytosome formulation, for COVID-19 prophylaxis and adjuvant therapy.

Reviews covering quercetin for COVID-19 include1-20.

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1. Sanduzzi Zamparelli et al., Immune-Boosting and Antiviral Effects of Antioxidants in COVID-19 Pneumonia: A Therapeutic Perspective, Life, doi:10.3390/life15010113.mdpi.com, doi.org.

2. Duan et al., Bioactive compounds,quercetin, curcumin and β-glucan,regulate innate immunity via the gut-liver-brain axis, Trends in Food Science & Technology, doi:10.1016/j.tifs.2024.104864.sciencedirect.com, doi.org.

3. Beşler et al., Investigation of potential effects of quercetin on COVID-19 treatment: a systematic review of randomized controlled trials, Clinical Science of Nutrition, doi:10.62210/ClinSciNutr.2024.86.clinscinutr.org, doi.org.

4. Ho et al., Therapeutic Implications of Quercetin and its Derived-products in COVID-19 Protection and Prophylactic, Heliyon, doi:10.1016/j.heliyon.2024.e30080.sciencedirect.com, doi.org.

5. Vajdi et al., Effect of polyphenols against complications of COVID-19: current evidence and potential efficacy, Pharmacological Reports, doi:10.1007/s43440-024-00585-6.springer.com, doi.org.

6. Chen et al., Effect and mechanism of quercetin or quercetin‐containing formulas against COVID‐19: From bench to bedside, Phytotherapy Research, doi:10.1002/ptr.8175.wiley.com, doi.org.

7. Yong et al., Natural Products-Based Inhaled Formulations for Treating Pulmonary Diseases, International Journal of Nanomedicine, doi:10.2147/ijn.s451206.dovepress.com, doi.org.

8. Agrawal et al., Antiviral Significance of Isoquercetin (Quercetin-3-O-Glucoside) With Special Reference to its Anti-Coronaviral Potential, Natural Product Communications, doi:10.1177/1934578X231219560.sagepub.com, doi.org.

9. Matías-Pérez et al., Relationship of quercetin intake and oxidative stress in persistent Covid, Frontiers in Nutrition, doi:10.3389/fnut.2023.1278039.frontiersin.org, doi.org.

10. Georgiou et al., Quercetin: A Potential Polydynamic Drug, Molecules, doi:10.3390/molecules28248141.mdpi.com, doi.org.

11. Donzelli, A., Neglected Effective Early Therapies against COVID-19: Focus on Functional Foods and Related Active Substances. A Review, MDPI AG, doi:10.20944/preprints202312.1178.v1.preprints.org, doi.org.

12. Dinda et al., Anti-SARS-CoV-2, antioxidant and immunomodulatory potential of dietary flavonol quercetin: Focus on molecular targets and clinical efficacy, European Journal of Medicinal Chemistry Reports, doi:10.1016/j.ejmcr.2023.100125.sciencedirect.com, doi.org.

13. Mirza et al., Quercetin as a Therapeutic Product: Evaluation of Its Pharmacological Action and Clinical Applications—A Review, Pharmaceuticals, doi:10.3390/ph16111631.mdpi.com, doi.org.

14. Massimo Magro et al., Use of Quercetin for Therapeutic Purposes in COVID-19 Infections: The Opinion of the Geriatrician Doctor, Journal of Modern Biology and Drug Discovery, doi:10.53964/jmbdd.2023004.innovationforever.com, doi.org.

15. Shorobi et al., Quercetin: A Functional Food-Flavonoid Incredibly Attenuates Emerging and Re-Emerging Viral Infections through Immunomodulatory Actions, Molecules, doi:10.3390/molecules28030938.mdpi.com, doi.org.

16. Gasmi et al., Quercetin in the Prevention and Treatment of Coronavirus Infections: A Focus on SARS-CoV-2, Pharmaceuticals, doi:10.3390/ph15091049.mdpi.com, doi.org.

17. Rizky et al., The pharmacological mechanism of quercetin as adjuvant therapy of COVID-19, Life Research, doi:10.53388/life2022-0205-302.tmrjournals.com, doi.org.

18. Imran 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/antiox11050876.mdpi.com, doi.org.

19. Derosa et al., A role for quercetin in coronavirus disease 2019 (COVID-19), Phytotherapy Research, doi:10.1002/ptr.6887.wiley.com, doi.org.

20. Biancatelli et al., Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19), Frontiers in Immunology, doi:10.3389/fimmu.2020.01451.frontiersin.org, doi.org.

Rizky et al., 15 May 2022, peer-reviewed, 5 authors.

This Paper Quercetin All

Wahyu Choirur Rizky, Muhammad Candragupta Jihwaprani, Avicena Al Kindi, Arif Nur, Muhammad Ansori, Mazhar Mushtaq

doi:10.53388/life2022-0202-302

oral supplements such as zinc, vitamin C, vitamin D, folic acid [5] , and flavonoids such as quercetin, as adjuvant pharmacotherapy in the management of . Quercetin (3, 3', 4', 5, 7-pentahydroxyfl avone) (C15H10O7) is a major polyphenol that belongs to the fl avonoid family. It is categorized as fl avonol, one of the six subclasses of fl avonoid compounds. Being the most abundant form of flavonoid molecules, quercetins are ubiquitously distributed in a variety of dietary plants, including apple, berries, onion, kale, tea, tomato, grape, as well as nuts. Furthermore, it is also aff ordably marketed in the form of tablet dietary supplements. Various in vitro and animal model studies have shown that quercetin has numerous physiological eff ects, including antioxidant, anti-infl ammatory, immunomodulatory, and antiviral properties. There is well-documented evidence pointing toward its eff ects in attenuating lipid peroxidation, platelet aggregation, and capillary permeability, which cumulatively result in cardioprotective eff ects, as well as anti-carcinogenic properties [7] . Too few human studies address the effectiveness of quercetin, specifically in the management of viral respiratory infection. Notwithstanding, some human studies have provided signifi cant results in specifi c populations with non-infectious causes of respiratory disease [8] [9] [10] [11] . Current evidence shows the specific pathomechanics of COVID-19-associated acute respiratory distress syndrome (CARDS), which include severe inflammation and pulmonary edema leading to impaired alveolar homeostasis, and alteration of lung physiology, and resulting in lung fi brosis, infl ammation of endothelium, vascular thrombosis, as well as an exaggerated immune response [12] . during the writing of this review [2] . Ergo, scientists and researchers are racing the clock and breaking records to develop COVID-19 vaccines and repurpose several therapeutic options to treat mild to severe COVID-19. Recently, albeit several trials that are underway to produce safe and effective vaccines, in conjunction with its distribution, over 4.9 million vaccine doses have been administered worldwide and obtained emergency use authorization by The United States food and drug administration (FDA) [2] . However, an approach called drug repurposed under ACTIV-6 protocol has been created by the national institute of health (NIH) to explore a pool of up to seven drugs approved by the FDA for other diseases, particularly antiviral drug remdesivir, the anti-infl ammatory baricitinib, and corticosteroid (e.g. dexamethasone) for treating mild to moderate 4] . Furthermore, there have been numerous ongoing trials evaluating

Funding The authors received no specifi c funding for this work. Author contribution All authors contributed equally to the manuscript and read and approved the fi nal version of the manuscript. Competing interests The authors declare no confl icts of interest. Abbreviations TCMSP, traditional Chinese medicine systems pharmacology; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; ACE2, angiotensin-converting enzyme 2; Mpro, main protease; 3CLpro, 3C-like protease; PLpro, Papain-like protease; RdRP, RNA-dependent RNA polymerase; COVID-19, Coronavirus Disease; NIH, national institute of health; CARDS, COVID-19-associated acute respiratory distress syndrome; SARS-CoV, SARS-Associated Coronavirus; MERS-CoV, Middle East respiratory syndrome coronavirus; WHO, World Health Organization; FDA, food and drug administration; SPR, Surface Plasmon Resonance; GO, Gene Ontology; rhACE2, recombinant human ACE2; IC50, inhibitory concentration; GEO, gene expression omnibus; SPR/FRET, surface plasmon resonance/fl uorescence resonance energy transfer; GSEA, Gene Set Enrichment Analyses; ITC, Isothermal titration calorimetry; WURSS, Wisconsin Upper Respiratory Symptom Survey; SFT-PC, surfactant protein-C; RDNI, Reduning Injection Peer review information Life Research thanks Kaloyan Asenov Kaloyanov, George Kluck, Sergio Sanchez Gambetta Dong Zhao Pratichi Singh Pravin D. Potdar for their contribution to the peer review of this paper.

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