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The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach

Mansouri et al., Scientific Reports, doi:10.1038/s41598-022-04778-y

Jan 2022

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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.

5,100+ studies for 112 treatments. c19early.org

In Silico study predicting that calcitriol and estradiol disrupt the interaction between the SARS-CoV-2 spike protein and ACE2. Authors note that calcitriol may be more effective in the presence of estradiol.

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

8 In Silico studies1-8

12 In Vitro studies9-20

3 In Vivo animal studies12,16,21

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 function22-25. Vitamin D inhibits SARS-CoV-2 replication in vitro12,19, mitigates lung inflammation, damage, and lethality in mice with an MHV-3 model for β-CoV respiratory infections12,19, reduces SARS-CoV-2 replication in nasal epithelial cells via increased type I interferon expression15, downregulates proinflammatory cytokines IL-1β and TNF-α in SARS-CoV-2 spike protein-stimulated cells11, attenuates nucleocapsid protein-induced hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway16, may be neuroprotective by protecting the blood-brain barrier, reducing neuroinflammation, and via immunomodulatory effects26, downregulates ACE2 and TMPRSS2 in human trophoblasts and minimizes spike protein-induced inflammation14, minimizes platelet aggregation mediated by SARS-CoV-2 spike protein via inhibiting integrin αIIbβ3 outside-in signaling10, and improves regulatory immune cell levels and control of proinflammatory cytokines in severe COVID-1927. Calcifediol inhibits SARS-CoV-2 papain-like protease (PLpro), a critical enzyme for viral replication9. Symptomatic COVID-19 is associated with a lower frequency of natural killer (NK) cells and vitamin D has been shown to improve NK cell activity28,29.

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1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

Mansouri et al., 13 Jan 2022, peer-reviewed, 5 authors. Contact: kowsarzar@yahoo.com, akiomiya@obihiro.ac.jp.

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

This Paper Vitamin D All

The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach

Alireza Mansouri, Rasoul Kowsar, Mostafa Zakariazadeh, Hassan Hakimi, Akio Miyamoto

Scientific Reports, doi:10.1038/s41598-022-04778-y

The novel coronavirus disease (COVID-19) is currently a big concern around the world. Recent reports show that the disease severity and mortality of COVID-19 infected patients may vary from gender to gender with a very high risk of death for seniors. In addition, some steroid structures have been reported to affect coronavirus, SARS-CoV-2, function and activity. The entry of SARS-CoV-2 into host cells depends on the binding of coronavirus spike protein to angiotensin converting enzyme-2 (ACE2). Viral main protease is essential for the replication of SARS-CoV-2. It was hypothesized that steroid molecules (e.g., estradiol, progesterone, testosterone, dexamethasone, hydrocortisone, prednisone and calcitriol) could occupy the active site of the protease and could alter the interaction of spike protein with ACE2. Computational data showed that estradiol interacted more strongly with the main protease active site. In the presence of calcitriol, the binding energy of the spike protein to ACE2 was increased, and transferring Apo to Locked S conformer of spike trimer was facilitated. Together, the interaction between spike protein and ACE2 can be disrupted by calcitriol. Potential use of estradiol and calcitriol to reduce virus invasion and replication needs clinical investigation. The novel coronavirus disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first recognized in the Hubei Province of China in December 2019 and has been reported as a very widespread disease with people-to-people transmission. Clinical evidence suggests that women are more resilient than men in terms of COVID-19 [1] [2] [3] [4] [5] . In the previous study, the critical factors involved in increasing the mortality and severity of COVID-19 in patients were investigated and higher disease severity and mortality were found in male patients 2 . It has been reported that 12.8% of 86 men died and 75.6% recovered, while 7.3% of 82 females died and 86.6% recovered 6 . In addition, the reports showed a relatively low risk of incidence in children but a very high risk of death in seniors 7 . Elderly patients diagnosed with COVID-19 aged 60 or older 8 had higher clinical signs, higher severity and longer periods of illness 9 . Sex steroid hormones are the primary cause of female and male differences. Testosterone (T) known as the predominant sex steroid hormone in males plays an essential role in sexual and reproductive development. In women, the predominant sex steroid hormones progesterone (P4) and estradiol (E2) are produced by ovaries. With respect to the menstrual cycle, the concentration of E2 reaches the highest level just before ovulation (during the follicular or proliferative phase) and then decreases shortly afterwards (during the luteal or secretory phase). P4 is released at peak level during the luteal phase, and then drops before the next menstrual period. Decreases in menopausal-associated ovarian hormones have been..

Author contributions Conceptualization: R.K., A.M.; Funding acquisition: R.K., A.M.; Investigation: Al.M., R.K., M.Z.; Methodology: Al.M., R.K., M.Z.; Software and Visualization: Al.M., M.Z.; Supervision: A.M., R.K.; Validation: Al.M., R.K., H.H., M.Z.; Writing-original draft: Al.M., R.K., M.Z., H.H.; Writing-review and editing: Al.M., R.K., M.Z., H.H., A.M. Competing interests The authors declare no competing interests. Additional information Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1038/ s41598-022-04778-y. Correspondence and requests for materials should be addressed to R.K. or A.M. Reprints and permissions information is available at www.nature.com/reprints. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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' 'Chem. 32, 2359–2368 (2011).', 'journal-title': 'J. Comput. Chem.'}, { 'key': '4778_CR62', 'doi-asserted-by': 'crossref', 'first-page': '1545', 'DOI': '10.1002/jcc.21287', 'volume': '30', 'author': 'BR Brooks', 'year': '2009', 'unstructured': 'Brooks, B. R. et al. CHARMM: The biomolecular simulation program. J. ' 'Comput. Chem. 30, 1545–1614 (2009).', 'journal-title': 'J. Comput. Chem.'}, { 'key': '4778_CR63', 'doi-asserted-by': 'crossref', 'first-page': '405', 'DOI': '10.1021/acs.jctc.5b00935', 'volume': '12', 'author': 'J Lee', 'year': '2016', 'unstructured': 'Lee, J. et al. CHARMM-GUI input generator for NAMD, GROMACS, AMBER, ' 'OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force ' 'field. J. Chem. Theory Comput. 12, 405–413 (2016).', 'journal-title': 'J. Chem. 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Today'}, { 'key': '4778_CR69', 'doi-asserted-by': 'crossref', 'first-page': '566', 'DOI': '10.1002/prot.340230412', 'volume': '23', 'author': 'D Frishman', 'year': '1995', 'unstructured': 'Frishman, D. & Argos, P. Knowledge-based protein secondary structure ' 'assignment. Proteins 23, 566–579 (1995).', 'journal-title': 'Proteins'}, { 'key': '4778_CR70', 'doi-asserted-by': 'crossref', 'first-page': '1136', 'DOI': '10.1021/ci025515j', 'volume': '42', 'author': 'IV Tetko', 'year': '2002', 'unstructured': 'Tetko, I. V. & Tanchuk, V. Y. Application of associative neural networks ' 'for prediction of lipophilicity in ALOGPS 2.1 program. J. Chem. Inform. ' 'Comput. Sci. 42, 1136–1145 (2002).', 'journal-title': 'J. Chem. Inform. Comput. Sci.'}, { 'key': '4778_CR71', 'doi-asserted-by': 'crossref', 'first-page': '127', 'DOI': '10.1093/protein/8.2.127', 'volume': '8', 'author': 'AC Wallace', 'year': '1995', 'unstructured': 'Wallace, A. C., Laskowski, R. A. & Thornton, J. M. 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