Indonesian Journal of Medical Chemistry and Bioinformatics


Syndrome Acute Respiratory Syndrome Corona Virus-2 (SARS COV2) is the virus that causes the COVID19 disease and has caused more than 4 million deaths worldwide. This virus infects the host cell through the interaction between the virus’s glycoprotein S molecule with the ACE2 which is the virus receptor, binding, undergoes membrane fusion and enters the cell and replicates in it. Currently, several strategies used in developing anti-viral compounds are targeting compounds that play a role in the process of entering the virus into host cells such as ACE2, S glycoprotein, and TMPRSS2, while some target main proteases such as RNA dependent Polymerase and N proteins. On the other hand, one of the causes for the worsening of COVID-19 cases is hyperinflammation. This condition can also be caused by an increase in calcium consumption activity which is responsible for the process of viral endocytosis, mast cell recruitment, and also the recruitment of surrounding cells to form syncytia. Under these conditions, virions that are trapped and accumulated in the syncytia can initiate the release of virions and pro-inflammatory molecules, leading to hyperinflammation and second week crash. This review will explain the importance of the role of calcium ions and mast cells in mediating inflammation as well as the prospect of inhibiting hyperinflammation in COVID19 using flavonoid compounds contained in daily food ingredients.

Bahasa Abstract

Sindrom Acute Respiratory Syndrome Corona Virus-2 (SARS COV2) adalah virus yang menyebabkan penyakit COVID19 dan telah menyebabkan lebih dari 4 juta kematian di seluruh dunia. Virus ini menginfeksi sel inang melalui interaksi antara molekul glikoprotein S virus dengan ACE2 yang merupakan reseptor virus, mengikat, mengalami fusi membran, dan masuk ke dalam sel, serta bereproduksi di dalamnya. Saat ini, beberapa strategi yang digunakan dalam mengembangkan senyawa anti-virus menargetkan senyawa yang berperan dalam proses masuknya virus ke dalam sel pembawa seperti ACE2, glikoprotein S, dan TMPRSS2, sementara beberapa lainnya menargetkan protease utama seperti RNA dependent Polymerase dan protein N . Di sisi lain, salah satu penyebab peningkatan kasus COVID-19 adalah hiperinflamasi. Kondisi ini antara lain dapat disebabkan oleh peningkatan aktivitas konsumsi kalsium yang bertanggung jawab dalam proses endositosis virus, rekrutmen sel mast, dan juga rekrutmen sel sekitarnya untuk membentuk sinkitia. Dalam kondisi ini, virion yang terjebak dan terakumulasi dalam sinkitia dapat mengawali pelepasan virion dan molekul pro-inflamasi, menyebabkan hiperinflamasi, dan second week crash. Tinjauan ini akan menjelaskan pentingnya peran ion kalsium dan sel mast dalam mediasi inflamasi serta prospek pemblokiran hiperinflamasi dalam COVID19 menggunakan senyawa flavonoid yang terkandung dalam bahan makanan sehari-hari.


1. Chowdhury R, Heng K, Shawon MSR, Goh G, Okonofua D, Ochoa-Rosales C, et al. Dynamic interventions to control COVID-19 pandemic: a multivariate prediction modelling study comparing 16 worldwide countries. Eur J Epidemiol. 2020 May 1;35(5):389–99.

2. Mathieu E, Ritchie H, Ortiz-Ospina E, Roser M, Hasell J, Appel C, et al. Author Correction: A global database of COVID-19 vaccinations. Nat Hum Behav. 2021 Jul;5(7):956–9.

3. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med. 2020 Nov 5;383(19):1813–26.

4. Axfors C, Schmitt AM, Janiaud P, van’t Hooft J, Abd-Elsalam S, Abdo EF, et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nat Commun. 2021 Apr 15;12(1):2349.

5. Bryant A, Lawrie TA, Dowswell T, Fordham EJ, Mitchell S, Hill SR, et al. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. Am J Ther [Internet]. 2021;28(4). Available from: https://journals.lww.com/americantherapeutics/Fulltext/2021/08000/Ivermectin_for_Prevention_and_Treatment_of.7.aspx

6. Horby PW, Mafham M, Bell JL, Linsell L, Staplin N, Emberson J, et al. Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. The Lancet. 2020 Oct 24;396(10259):1345–52.

7. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020 Mar 18;6(1):16.

8. White NJ, Watson JA, Hoglund RM, Chan XHS, Cheah PY, Tarning J. COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. PLOS Med. 2020 Sep 3;17(9):e1003252.

9. Gunst JD, Staerke NB, Pahus MH, Kristensen LH, Bodilsen J, Lohse N, et al. Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial. EClinicalMedicine [Internet]. 2021 May 1 [cited 2021 Oct 20];35. Available from: https://doi.org/10.1016/j.eclinm.2021.100849

10. Li Y, Liu D, Wang Y, Su W, Liu G, Dong W. The Importance of Glycans of Viral and Host Proteins in Enveloped Virus Infection. Front Immunol. 2021;12:1544.

11. Sztain T, Ahn S-H, Bogetti AT, Casalino L, Goldsmith JA, Seitz E, et al. A glycan gate controls opening of the SARS-CoV-2 spike protein. Nat Chem. 2021 Oct 1;13(10):963–8.

12. Casalino L, Gaieb Z, Goldsmith JA, Hjorth CK, Dommer AC, Harbison AM, et al. Beyond Shielding: The Roles of Glycans in the SARS-CoV-2 Spike Protein. ACS Cent Sci. 2020 Oct 28;6(10):1722–34.

13. Bussani R, Schneider E, Zentilin L, Collesi C, Ali H, Braga L, et al. Persistence of viral RNA, widespread thrombosis and abnormal cellular syncytia are hallmarks of COVID-19 lung pathology. medRxiv [Internet]. 2020; Available from: https://www.medrxiv.org/content/early/2020/06/26/2020.06.22.20136358

14. Braga L, Ali H, Secco I, Chiavacci E, Neves G, Goldhill D, et al. Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia. Nature. 2021 Jun 1;594(7861):88–93.

15. Arlt E, Fraticelli M, Tsvilovskyy V, Nadolni W, Breit A, O’Neill TJ, et al. TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity. Proc Natl Acad Sci. 2020 Jul 28;117(30):18068.

16. Wu M-L, Liu F-L, Sun J, Li X, He X-Y, Zheng H-Y, et al. SARS-CoV-2-Triggered Mast Cell Rapid Degranulation Induces Alveolar Epithelial Inflammation and Lung Injury. bioRxiv. 2021 Jan 1;2021.06.24.449680.

17. Greene MW, Roberts AP, Frugé AD. Negative Association Between Mediterranean Diet Adherence and COVID-19 Cases and Related Deaths in Spain and 23 OECD Countries: An Ecological Study. Front Nutr. 2021;8:74.

18. Zhang Z, Zheng Y, Niu Z, Zhang B, Wang C, Yao X, et al. SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination. Cell Death Differ. 2021 Sep 1;28(9):2765–77.

19. Lin L, Li Q, Wang Y, Shi Y. Syncytia formation during SARS-CoV-2 lung infection: a disastrous unity to eliminate lymphocytes. Cell Death Differ. 2021 Jun 1;28(6):2019–21.

20. Buchrieser J, Dufloo J, Hubert M, Monel B, Planas D, Rajah MM, et al. Syncytia formation by SARS-CoV-2-infected cells. EMBO J. 2021 Feb 1;40(3):e107405.

21. Zhou Y, Frey TK, Yang JJ. Viral calciomics: interplays between Ca2+ and virus. Cell Calcium. 2009/06/16 ed. 2009 Jul;46(1):1–17.

22. Di Filippo L, Formenti AM, Rovere-Querini P, Carlucci M, Conte C, Ciceri F, et al. Hypocalcemia is highly prevalent and predicts hospitalization in patients with COVID-19. Endocrine. 2020/06/12 ed. 2020 Jun;68(3):475–8.

23. di Filippo L, Doga M, Frara S, Giustina A. Hypocalcemia in COVID-19: Prevalence, clinical significance and therapeutic implications. Rev Endocr Metab Disord [Internet]. 2021 Apr 13; Available from: https://doi.org/10.1007/s11154-021-09655-z

24. Pal R, Ram S, Zohmangaihi D, Biswas I, Suri V, Yaddanapudi LN, et al. High Prevalence of Hypocalcemia in Non-severe COVID-19 Patients: A Retrospective Case-Control Study. Front Med. 2021;7:1057.

25. Motta Junior J da S, Miggiolaro AFR dos S, Nagashima S, de Paula CBV, Baena CP, Scharfstein J, et al. Mast Cells in Alveolar Septa of COVID-19 Patients: A Pathogenic Pathway That May Link Interstitial Edema to Immunothrombosis. Front Immunol. 2020;11:2369.

26. Ashmole I, Bradding P. Ion channels regulating mast cell biology. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2013 May;43(5):491–502.

27. Ma H-T, Beaven MA. Regulators of Ca2+ Signaling in Mast Cells: Potential Targets for Treatment of Mast Cell-Related Diseases? In: Gilfillan AM, Metcalfe DD, editors. Mast Cell Biology: Contemporary and Emerging Topics [Internet]. Boston, MA: Springer US; 2011. p. 62–90. Available from: https://doi.org/10.1007/978-1-4419-9533-9_5

28. Pearson H, Todd EJAA, Ahrends M, Hover SE, Whitehouse A, Stacey M, et al. TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection. Thorax. 2021 Jan 1;76(1):64.

29. Ueki H, Furusawa Y, Iwatsuki-Horimoto K, Imai M, Kabata H, Nishimura H, et al. Effectiveness of Face Masks in Preventing Airborne Transmission of SARS-CoV-2. mSphere. 2020 Oct 21;5(5).

30. Bai W, Liu M, Xiao Q. The diverse roles of TMEM16A Ca2+-activated Cl− channels in inflammation. J Adv Res. 2021 Nov 1;33:53–68.

31. Lee J, Park S-S, Kim TY, Lee D-G, Kim D-W. Lymphopenia as a Biological Predictor of Outcomes in COVID-19 Patients: A Nationwide Cohort Study. Cancers. 2021 Jan 26;13(3):471.

32. Al-Afif A, Alyazidi R, Oldford SA, Huang YY, King CA, Marr N, et al. Respiratory syncytial virus infection of primary human mast cells induces the selective production of type I interferons, CXCL10, and CCL4. J Allergy Clin Immunol. 2015 Nov 1;136(5):1346-1354.e1.

33. Glynne P, Tahmasebi N, Gant V, Gupta R. Long-COVID following mild SARS CoV-2 infection: characteristic T cell alterations and response to antihistamines. medRxiv. 2021 Jan 1;2021.06.06.21258272.

34. Bian H, Zheng Z-H, Wei D, Wen A, Zhang Z, Lian J-Q, et al. Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial. Signal Transduct Target Ther. 2021 May 17;6(1):194.

35. Zhou S, Butler-Laporte G, Nakanishi T, Morrison DR, Afilalo J, Afilalo M, et al. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity. Nat Med. 2021 Apr 1;27(4):659–67.

36. Tsutsui-Takeuchi M, Ushio H, Fukuda M, Yamada T, Niyonsaba F, Okumura K, et al. Roles of retinoic acid-inducible gene-I-like receptors (RLRs), Toll-like receptor (TLR) 3 and 2’-5’ oligoadenylate synthetase as viral recognition receptors on human mast cells in response to viral infection. Immunol Res. 2015 Mar;61(3):240–9.

37. Farooqui AA, Farooqui T. Chapter 27 - Importance of Fruit and Vegetable-Derived Flavonoids in the Mediterranean Diet: Molecular and Pathological Aspects. In: Farooqui T, Farooqui AA, editors. Role of the Mediterranean Diet in the Brain and Neurodegenerative Diseases [Internet]. Academic Press; 2018. p. 417–27. Available from: https://www.sciencedirect.com/science/article/pii/B9780128119594000274

38. Josephson RA, Silverman HS, Lakatta EG, Stern MD, Zweier JL. Study of the mechanisms of hydrogen peroxide and hydroxyl free radical-induced cellular injury and calcium overload in cardiac myocytes. J Biol Chem. 1991 Feb 5;266(4):2354–61.

39. Fonseca W, Malinczak C, Schuler C, Best S, Rasky A, Morris S, et al. Uric acid pathway activation during respiratory virus infection promotes Th2 immune response via innate cytokine production and ILC2 accumulation. Mucosal Immunol. 2020 Feb 11;13.

40. Schuler CF 4th, Malinczak C-A, Best SKK, Morris SB, Rasky AJ, Ptaschinski C, et al. Inhibition of uric acid or IL-1β ameliorates respiratory syncytial virus immunopathology and development of asthma. Allergy. 2020 Sep;75(9):2279–93.

41. Bitko V, Garmon NE, Cao T, Estrada B, Oakes JE, Lausch RN, et al. Activation of cytokines and NF-kappa B in corneal epithelial cells infected by respiratory syncytial virus: potential relevance in ocular inflammation and respiratory infection. BMC Microbiol. 2004 Jul 15;4(1):28.

42. Nagao A, Seki M, Kobayashi H. Inhibition of xanthine oxidase by flavonoids. Biosci Biotechnol Biochem. 1999 Oct;63(10):1787–90.

43. Ramadhanti NS, Kusuma WA, Heryanto R. Development of Jamu formula prediction system module of Ijah analytics based on pharmacology activity and particular efficacy target. IOP Conf Ser Earth Environ Sci. 2019 Oct 28;335:012003.

44. Zhang X, Li H, Zhang H, Liu Y, Huo L, Jia Z, et al. Inhibition of transmembrane member 16A calcium-activated chloride channels by natural flavonoids contributes to flavonoid anticancer effects. Br J Pharmacol. 2017 Jul;174(14):2334–45.

45. Kato M, Takayama Y, Sunagawa M. The Calcium-Activated Chloride Channel TMEM16A is Inhibitied by Liquiritigenin. Front Pharmacol. 2021 Apr 8;12:628968–628968.

46. Namkung W, Thiagarajah JR, Phuan P-W, Verkman AS. Inhibition of Ca2+-activated Cl- channels by gallotannins as a possible molecular basis for health benefits of red wine and green tea. FASEB J Off Publ Fed Am Soc Exp Biol. 2010/06/25 ed. 2010 Nov;24(11):4178–86.

47. Guo S, Bai X, Liu Y, Shi S, Wang X, Zhan Y, et al. Inhibition of TMEM16A by Natural Product Silibinin: Potential Lead Compounds for Treatment of Lung Adenocarcinoma. Front Pharmacol. 2021;12:643489.

48. Suzuki T, Suzuki J, Nagata S. Functional swapping between transmembrane proteins TMEM16A and TMEM16F. J Biol Chem. 2014/01/28 ed. 2014 Mar 14;289(11):7438–47.

49. Kempuraj D, Madhappan B, Christodoulou S, Boucher W, Cao J, Papadopoulou N, et al. Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells. Br J Pharmacol. 2005 Aug;145(7):934–44.

50. Seelinger G, Merfort I, Schempp CM. Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Med. 2008 Nov;74(14):1667–77.