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A new investigation into the molecular mechanism of cholecalciferol towards reducing cytokines storm

Alzahrani, A., Octahedron Drug Research, doi:10.21608/odr.2024.308273.1043

Jan 2025

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Vitamin D for COVID-19

8th treatment shown to reduce risk in October 2020, now with p < 0.00000000001 from 122 studies, recognized in 9 countries.

Lower risk for mortality, ICU, hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,300+ studies for 115 treatments. c19early.org

In Silico study showing that cholecalciferol (vitamin D3) exhibits strong binding affinity to multiple cytokines involved in cytokine storm, with binding energies exceeding -6.5 kcal/mol. Molecular dynamics simulations revealed remarkable stability of cholecalciferol-cytokine complexes. Pharmacokinetic analysis suggests cholecalciferol has favorable absorption, distribution, metabolism, and excretion properties. Authors propose cholecalciferol may help reduce cytokine storm and alleviate severe COVID-19 symptoms by modulating the immune response and dampening excessive cytokine production.

24 preclinical studies support the efficacy of vitamin D for COVID-19:

9 In Silico studies1-9

12 In Vitro studies10-21

3 In Vivo animal studies13,17,22

Vitamin D has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function23-26. Vitamin D inhibits SARS-CoV-2 replication in vitro13,20, mitigates lung inflammation, damage, and lethality in mice with an MHV-3 model for β-CoV respiratory infections13,20, reduces SARS-CoV-2 replication in nasal epithelial cells via increased type I interferon expression16, downregulates proinflammatory cytokines IL-1β and TNF-α in SARS-CoV-2 spike protein-stimulated cells12, attenuates nucleocapsid protein-induced hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway17, may be neuroprotective by protecting the blood-brain barrier, reducing neuroinflammation, and via immunomodulatory effects27, downregulates ACE2 and TMPRSS2 in human trophoblasts and minimizes spike protein-induced inflammation15, may minimize cytokine storm by dampening excessive cytokine production1, minimizes platelet aggregation mediated by SARS-CoV-2 spike protein via inhibiting integrin αIIbβ3 outside-in signaling11, and improves regulatory immune cell levels and control of proinflammatory cytokines in severe COVID-1928. Calcifediol inhibits SARS-CoV-2 papain-like protease (PLpro), a critical enzyme for viral replication10. Symptomatic COVID-19 is associated with a lower frequency of natural killer (NK) cells and vitamin D has been shown to improve NK cell activity29,30.

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1. Alzahrani, A., A new investigation into the molecular mechanism of cholecalciferol towards reducing cytokines storm, Octahedron Drug Research, doi:10.21608/odr.2024.308273.1043.ekb.eg, doi.org.

2. Haque et al., Exploring potential therapeutic candidates against COVID-19: a molecular docking study, Discover Molecules, doi:10.1007/s44345-024-00005-5.springer.com, doi.org.

3. Morales-Bayuelo et al., New findings on ligand series used as SARS-CoV-2 virus inhibitors within the frameworks of molecular docking, molecular quantum similarity and chemical reactivity indices, F1000Research, doi:10.12688/f1000research.123550.3.f1000research.com, doi.org.

4. Chellasamy et al., Docking and molecular dynamics studies of human ezrin protein with a modelled SARS-CoV-2 endodomain and their interaction with potential invasion inhibitors, Journal of King Saud University - Science, doi:10.1016/j.jksus.2022.102277.sciencedirect.com, doi.org.

5. Pandya et al., Unravelling Vitamin B12 as a potential inhibitor against SARS-CoV-2: A computational approach, Informatics in Medicine Unlocked, doi:10.1016/j.imu.2022.100951.sciencedirect.com, doi.org.

6. Mansouri et al., The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach, Scientific Reports, doi:10.1038/s41598-022-04778-y.nature.com, doi.org.

7. Song et al., Vitamin D3 and its hydroxyderivatives as promising drugs against COVID-19: a computational study, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1964601.tandfonline.com, doi.org.

8. Qayyum et al., Vitamin D and lumisterol novel metabolites can inhibit SARS-CoV-2 replication machinery enzymes, Endocrinology and Metabolism, doi:10.1152/ajpendo.00174.2021.physiology.org, doi.org.

9. Al-Mazaideh et al., Vitamin D is a New Promising Inhibitor to the Main Protease (Mpro) of COVID-19 by Molecular Docking, Journal of Pharmaceutical Research International, doi:10.9734/jpri/2021/v33i29B31603.journaljpri.com, doi.org.

10. Chen et al., In Vitro Characterization of Inhibition Function of Calcifediol to the Protease Activity of SARS-COV-2 PLpro, Journal of Medical Virology, doi:10.1002/jmv.70085.wiley.com, doi.org.

11. Wang et al., 1,25‐Dihydroxyvitamin D3 attenuates platelet aggregation potentiated by SARS‐CoV‐2 spike protein via inhibiting integrin αIIbβ3 outside‐in signaling, Cell Biochemistry and Function, doi:10.1002/cbf.4039.wiley.com, doi.org.

12. Alcalá-Santiago et al., Disentangling the Immunomodulatory Effects of Vitamin D on the SARS-CoV-2 Virus by In Vitro Approaches, The 14th European Nutrition Conference FENS 2023, doi:10.3390/proceedings2023091415.mdpi.com, doi.org.

13. Campolina-Silva et al., Dietary Vitamin D Mitigates Coronavirus-Induced Lung Inflammation and Damage in Mice, Viruses, doi:10.3390/v15122434.mdpi.com, doi.org.

14. Moatasim et al., Potent Antiviral Activity of Vitamin B12 against Severe Acute Respiratory Syndrome Coronavirus 2, Middle East Respiratory Syndrome Coronavirus, and Human Coronavirus 229E, Microorganisms, doi:10.3390/microorganisms11112777.mdpi.com, doi.org.

15. Vargas-Castro et al., Calcitriol prevents SARS-CoV spike-induced inflammation in human trophoblasts through downregulating ACE2 and TMPRSS2 expression, The Journal of Steroid Biochemistry and Molecular Biology, doi:10.1016/j.jsbmb.2024.106625.sciencedirect.com, doi.org.

16. Sposito et al., Age differential CD13 and interferon expression in airway epithelia affect SARS-CoV-2 infection - effects of vitamin D, Mucosal Immunology, doi:10.1016/j.mucimm.2023.08.002.nih.gov, doi.org.

17. Chen (B) et al., Vitamin D3 attenuates SARS‐CoV‐2 nucleocapsid protein‐caused hyperinflammation by inactivating the NLRP3 inflammasome through the VDR‐BRCC3 signaling pathway in vitro and in vivo, MedComm, doi:10.1002/mco2.318.wiley.com, doi.org.

18. Rybakovsky et al., Calcitriol modifies tight junctions, improves barrier function, and reduces TNF‐α‐induced barrier leak in the human lung‐derived epithelial cell culture model, 16HBE 14o‐, Physiological Reports, doi:10.14814/phy2.15592.wiley.com, doi.org.

19. DiGuilio et al., The multiphasic TNF-α-induced compromise of Calu-3 airway epithelial barrier function, Experimental Lung Research, doi:10.1080/01902148.2023.2193637.tandfonline.com, doi.org.

20. Pickard et al., Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells, PLOS Pathogens, doi:10.1371/journal.ppat.1009840.plos.org, doi.org.

21. Mok et al., Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis, bioRxiv, doi:10.1101/2020.06.21.162396.biorxiv.org, doi.org.

22. Fernandes de Souza et al., Lung Inflammation Induced by Inactivated SARS-CoV-2 in C57BL/6 Female Mice Is Controlled by Intranasal Instillation of Vitamin D, Cells, doi:10.3390/cells12071092.mdpi.com, doi.org.

23. Galmés et al., Suboptimal Consumption of Relevant Immune System Micronutrients Is Associated with a Worse Impact of COVID-19 in Spanish Populations, Nutrients, doi:10.3390/nu14112254.mdpi.com, doi.org.

24. Galmés (B) et al., Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework, Nutrients, doi:10.3390/nu12092738.mdpi.com, doi.org.

25. EFSA, Scientific Opinion on the substantiation of a health claim related to vitamin D and contribution to the normal function of the immune system pursuant to Article 14 of Regulation (EC) No 1924/2006, EFSA Journal, doi:10.2903/j.efsa.2015.4096.europa.eu, doi.org.

26. EFSA (B), Scientific Opinion on the substantiation of health claims related to vitamin D and normal function of the immune system and inflammatory response (ID 154, 159), maintenance of normal muscle function (ID 155) and maintenance of normal cardiovascular function (ID 159) pursuant to Article 13(1) of Regulation (E, EFSA Journal, doi:10.2903/j.efsa.2010.1468.wiley.com, doi.org.

27. Gotelli et al., Understanding the immune-endocrine effects of vitamin D in SARS-CoV-2 infection: a role in protecting against neurodamage?, Neuroimmunomodulation, doi:10.1159/000533286.karger.com, doi.org.

28. Saheb Sharif-Askari et al., Increased blood immune regulatory cells in severe COVID-19 with autoantibodies to type I interferons, Scientific Reports, doi:10.1038/s41598-023-43675-w.nature.com, doi.org.

29. Graydon et al., High baseline frequencies of natural killer cells are associated with asymptomatic SARS-CoV-2 infection, Current Research in Immunology, doi:10.1016/j.crimmu.2023.100064.sciencedirect.com, doi.org.

30. Oh et al., Vitamin D and Exercise Are Major Determinants of Natural Killer Cell Activity, Which Is Age- and Gender-Specific, Frontiers in Immunology, doi:10.3389/fimmu.2021.594356.frontiersin.org, doi.org.

Alzahrani et al., 1 Jan 2025, multiple countries, peer-reviewed, 1 author. Contact: alzharaniaar@bu.edu.sa (corresponding author).

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Vitamin D All

A new investigation into the molecular mechanism of cholecalciferol towards reducing cytokines storm

Abdulaziz Alzahrani

Cytokine storm, also referred to as cytokine release syndrome (CRS), is a condition characterized by an excessive production of inflammatory signals by the immune system, potentially leading to organ failure and death. This phenomenon has garnered significant attention due to its association with the COVID-19 pandemic, wherein it appears to contribute to severe symptoms in certain individuals infected with the SARS-CoV-2 virus. In efforts to combat cytokine storm, researchers have explored natural substances as potential therapeutics. In this study, we investigated the efficacy of cholecalciferol in targeting key cytokines involved in cytokine storm. Through molecular docking analyses, molecular dynamics simulations, and assessment of pharmacokinetic properties, we evaluated the stability and potential of cholecalciferol in mitigating cytokine storm. Our findings indicate that cholecalciferol exhibits strong binding affinity with several cytokines, with binding energies exceeding -6.5 kcal/mol. Furthermore, post-molecular dynamics analysis revealed remarkable stability of cholecalciferol with these cytokines. Pharmacokinetic measurements further supported its potential as a therapeutic agent, demonstrating favorable characteristics in terms of absorption, distribution, metabolism, and excretion. This research suggests that cholecalciferol may hold promise in reducing cytokine storm and alleviating severe symptoms associated with conditions such as COVID-19.

Ethical consideration: All the participants in this study gave their informed permission. Conflicts of Interest No conflicts of interest are disclosed.

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