Vitamin C promotes ACE2 degradation and protects against SARS‐CoV‐2 infection

Zuo et al., EMBO reports, doi:10.15252/embr.202256374, Jul 2022 (preprint)

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Vitamin C for COVID-19

6th treatment shown to reduce risk in September 2020, now with p = 0.00000002 from 75 studies, recognized in 22 countries.

Lower risk for mortality, ICU, hospitalization, and recovery.

No treatment is 100% effective. Protocols combine treatments.

5,700+ studies for 161 treatments. c19early.org

In Vitro and mouse study showing that vitamin C inhibits SARS-CoV-2. Vitamin C lowered ACE2 protein levels in a dose-dependent manner at a concentration of 1-10mM in both cell and humanized ACE2 mouse models.

16 preclinical studies support the efficacy of vitamin C for COVID-19:

7 In Silico studies1-7

8 In Vitro studies1,6,8-13

1 In Vivo animal study11

Vitamin C has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function14-16. Vitamin C plays a key role in the immune system, supporting the production and function of leukocytes, or white blood cells, which defend against infection and disease, including the production of lymphocytes, which make antibodies, and enhancing phagocytosis, the process by which immune system cells ingest and destroy viruses and infected cells. Vitamin C is an antioxidant, protecting cells from damage caused by free radicals. Vitamin C inhibits SARS-CoV-2 3CL^pro6,10, inhibits SARS-CoV-2 infection by reducing ACE2 levels in a dose-dependent manner11, and may limit COVID-19 induced cardiac damage by acting as an antioxidant and potentially reducing the reactive oxygen species (ROS) production induced by the spike protein that contributes to the activation of profibrotic pathways8. Vitamin C reduces inflammation, oxidative stress, and NETosis, supporting immune function and vascular protection17. Intracellular levels of vitamin C decline during COVID-19 hospitalization suggesting ongoing utilization and depletion of vitamin C18. Threonic acid, a metabolite of vitamin C, is lower in mild and severe cases, consistent with increased need for and metabolization of vitamin C with moderate infection, but more limited ability to produce threonic acid in severe infection due to depletion or existing lower levels of vitamin C19. Symptomatic COVID-19 is associated with a lower frequency of natural killer (NK) cells, and vitamin C has been shown to improve NK cell numbers and functioning20,21.

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1. Najimi et al., Phytochemical Inhibitors of SARS‐CoV‐2 Entry: Targeting the ACE2‐RBD Interaction with l‐Tartaric Acid, l‐Ascorbic Acid, and Curcuma longa Extract, ChemistrySelect, doi:10.1002/slct.202406035.wiley.com, doi.org.

2. Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.scienceopen.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. Alkafaas et al., A study on the effect of natural products against the transmission of B.1.1.529 Omicron, Virology Journal, doi:10.1186/s12985-023-02160-6.biomedcentral.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. Malla et al., Vitamin C inhibits SARS coronavirus-2 main protease essential for viral replication, bioRxiv, doi:10.1101/2021.05.02.442358.biorxiv.org, doi.org.

7. Kumar et al., In silico virtual screening-based study of nutraceuticals predicts the therapeutic potentials of folic acid and its derivatives against COVID-19, VirusDisease, doi:10.1007/s13337-020-00643-6.springer.com, doi.org.

8. Van Tin et al., Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis through NLRP3 Inflammasomes and NF-κB Signaling, Cells, doi:10.3390/cells13161331.mdpi.com, doi.org.

9. 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.

10. Đukić et al., Inhibition of SARS-CoV-2 Mpro with Vitamin C, L-Arginine and a Vitamin C/L-Arginine Combination, Frontiers in Bioscience-Landmark, doi:10.31083/j.fbl2801008.imrpress.com, doi.org.

11. Zuo et al., Vitamin C promotes ACE2 degradation and protects against SARS‐CoV‐2 infection, EMBO reports, doi:10.15252/embr.202256374.wiley.com, doi.org.

12. Hajdrik et al., In Vitro Determination of Inhibitory Effects of Humic Substances Complexing Zn and Se on SARS-CoV-2 Virus Replication, Foods, doi:10.3390/foods11050694.mdpi.com, doi.org.

13. Goc et al., Inhibitory effects of specific combination of natural compounds against SARS-CoV-2 and its Alpha, Beta, Gamma, Delta, Kappa, and Mu variants, European Journal of Microbiology and Immunology, doi:10.1556/1886.2021.00022.akjournals.com, doi.org.

14. 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.

15. 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.

16. EFSA, Scientific Opinion on the substantiation of health claims related to vitamin C and protection of DNA, proteins and lipids from oxidative damage (ID 129, 138, 143, 148), antioxidant function of lutein (ID 146), maintenance of vision (ID 141, 142), collagen formation (ID 130, 131, 136, 137, 149), function of the nervous system (ID 133), function of the immune system (ID 134), function of the immune system during and after extreme physical exercise (ID 144), non-haem iron absorption (ID 132, 147), energy-yielding metabolism (ID 135), and relief in case of irritation in the upper respiratory tract (ID 1714, 1715) pursuant to Article 13(1) of Regulation (EC) No 1924/2006, EFSA Journal, doi:10.2903/j.efsa.2009.1226.europa.eu, doi.org.

17. Xie et al., The role of reactive oxygen species in severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection-induced cell death, Cellular & Molecular Biology Letters, doi:10.1186/s11658-024-00659-6.biomedcentral.com, doi.org.

18. Boerenkamp et al., Low Levels of Serum and Intracellular Vitamin C in Hospitalized COVID-19 Patients, Nutrients, doi:10.3390/nu15163653.mdpi.com, doi.org.

19. Albóniga et al., Differential abundance of lipids and metabolites related to SARS-CoV-2 infection and susceptibility, Scientific Reports, doi:10.1038/s41598-023-40999-5.nature.com, doi.org.

20. 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.

21. Vojdani et al., In vivo effect of ascorbic acid on enhancement of human natural killer cell activity, Nutrition Research, doi:10.1016/S0271-5317(05)80799-7.sciencedirect.com, doi.org.

Zuo et al., 15 Jul 2022, China, peer-reviewed, 15 authors. Contact: huizheng@suda.edu.cn (corresponding author).

This Paper Vitamin C All

Abstract: bioRxiv preprint doi: https://doi.org/10.1101/2022.07.14.499651; this version posted July 15, 2022. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Vitamin C is an efficient natural product for prevention of 2 SARS-CoV-2 infection by targeting ACE2 in both cell and in 3 vivo mouse models 4 5 Yibo Zuo,1,2 Zhijin Zheng,1,2 Yingkang Huang,5 Jiuyi He,1,2 Lichao Zang,4 6 Tengfei Ren,1,2 Xinhua Cao,1,2 Ying Miao,1,2 Yukang Yuan,1,2 Yanli Liu,3 Feng 7 Ma,5 Sheng Tian,3 Jianfeng Dai,1,2 Qiang Ding,6 Hui Zheng1,2,7,* 8 9 1 International Institute of Infection and Immunity, Institutes of Biology and Medical 10 Sciences, Suzhou 11 2 Jiangsu Key Laboratory of Infection and Immunity, Suzhou 12 3 College of Pharmaceutical Sciences, Suzhou 13 4 The Third Affiliated Hospital of Soochow University, Changzhou 14 Soochow University, Jiangsu 215123, China 15 5 16 of Medical Sciences and Peking Union Medical College, Beijing 10005; Suzhou 17 Institute of Systems Medicine, Jiangsu 215123, China 18 6 19 Innovation Center for Structural Biology, Tsinghua University, Beijing 10084, China 20 7 21 *Correspondence: huizheng@suda.edu.cn CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy Center for Infectious Disease Research, School of Medicine, Beijing Advanced Lead contact 22 23 24 1 bioRxiv preprint doi: https://doi.org/10.1101/2022.07.14.499651; this version posted July 15, 2022. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 25 SUMMARY 26 ACE2 is a major receptor for cell entry of SARS-CoV-2. Despite advances in 27 targeting ACE2 to inhibit SARS-CoV-2's binding, how to efficiently and flexibly 28 control ACE2 levels for prevention of SARS-CoV-2 infection has not been 29 explored. Here, we revealed Vitamin C (VitC) administration as an effective 30 strategy to prevent SARS-CoV-2 infection. VitC reduced ACE2 protein levels in 31 a dose-dependent manner, while partial reduction of ACE2 can greatly restrict 32 SARS-CoV-2 infection. Further studies uncovered that USP50 is a crucial 33 regulator of ACE2 protein levels, and VitC blocks the USP50-ACE2 interaction, 34 thus promoting K48-linked polyubiquitination at Lys788 and degradation of 35 ACE2, without disrupting ACE2 transcriptional expression. Importantly, VitC 36 administration reduced host ACE2 and largely blocked SARS-CoV-2 infection 37 in mice. This study identified an in vivo ACE2 balance controlled by both 38 USP50 and an essential nutrient VitC, and revealed a critical role and 39 application of VitC in daily protection from SARS-CoV-2 infection. 40 41 Highlights 42 VitC reduces ACE2 protein levels in a dose-dependent manner 43 VitC and USP50 regulate K48-linked ubiquitination at Lys788 of ACE2 44 VitC blocks the interaction between USP50 and ACE2 45 VitC administration lowers host ACE2 and prevents SARS-CoV-2 infection 46 in vivo 47 48 2 bioRxiv preprint doi: https://doi.org/10.1101/2022.07.14.499651; this version posted July 15, 2022. The copyright holder for this preprint (which was not certified by..

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