Inhibition of SARS-CoV-2 Mpro with Vitamin C, L-Arginine and a Vitamin C/L-Arginine Combination

Đukić et al., Frontiers in Bioscience-Landmark, doi:10.31083/j.fbl2801008, Jan 2023

Source

PDF

All
Studies

Meta
Analysis

https://c19early.org/dukic.html

Vitamin C for COVID-19

6th treatment shown to reduce risk in September 2020, now with p = 0.00000004 from 74 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 135 treatments. c19early.org

In Vitro study showing inhibition of SARS-CoV-2 M^pro with vitamin C, L-arginine, and improved inhibition with the combination of both.

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.

Important missing comments or errors? Let us know.

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.

Đukić et al., 13 Jan 2023, peer-reviewed, 9 authors. Contact: sanja@vinca.rs (corresponding author).

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

This Paper Vitamin C All

Inhibition of SARS-CoV-2 Mpro with Vitamin C, L-Arginine and a Vitamin C/L-Arginine Combination

Ivana Đukić, Nevena Kaličanin, Milan Sencanski, Snezana B Pajovic, Jelena Milicevic, Jelena Prljic, Slobodan Paessler, Radivoje Prodanović, Sanja Glisic

Frontiers in Bioscience-Landmark, doi:10.31083/j.fbl2801008

Background: Drug resistance is a critical problem in health care that affects therapy outcomes and requires new approaches to drug design. SARS-CoV-2 M pro mutations are of concern as they can potentially reduce therapeutic efficacy. Viral infections are amongst the many disorders for which nutraceuticals have been employed as an adjunct therapy. The aim of this study was to examine the potential in vitro activity of L-arginine and vitamin C against SARS-CoV-2 M pro . Methods: The M pro inhibition assay was developed by cloning, expression, purification, and characterization of M pro . Selected compounds were then screened for protease inhibition. Results: Larginine was found to be active against SARS-CoV-2 M pro , while a vitamin C/L-arginine combination had a synergistic antiviral action against M pro . These findings confirm the results of our previous in silico repurposing study that showed L-arginine and vitamin C were potential M pro inhibitors. Moreover, they suggest a possible molecular mechanism to explain the beneficial effect of arginine in COVID patients. Conclusions: The findings of the current study are important because they help to identify COVID-19 treatments that are efficient, inexpensive, and have a favorable safety profile. The results of this study also suggest a possible adjuvant nutritional strategy for COVID-19 that could be used in conjunction with pharmacological agents.

Author Contributions Conceptualization-RP, SP and SG; performed the experiments-RP, NK, and IĐ; validation-NK, and RP; analyzed the data-NK, IĐ, MS, and RP; investigation-NK, IĐ, and MS; resources-RP; writing, original draft preparation-RP, SG, MS, SBP, JM and JP; writing, review and editing-SG, SBP, MS, SP and RP; visualization-IĐ, NK, RP; supervision-RP; project administration-RP, SG, JM, and MS. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. Ethics Approval and Consent to Participate Not applicable. Conflict of Interest The authors declare no conflict of interest.

References

Abobaker, Alzwi, Alraied, Overview of the possible role of vitamin C in management of COVID-19, Pharmacological Reports

Alvares, Conte-Junior, Silva, Paschoalin, Acute L-Arginine supplementation does not increase nitric oxide production in healthy subjects, Nutrition & Metabolism

Bogdański, Suliburska, Szulińska, Sikora, Walkowiak et al., L-Arginine and vitamin C attenuate proatherogenic effects of high-fat diet on biomarkers of endothelial dysfunction in rats, Biomedicine & Pharmacotherapy

Chen, Liu, Gao, Sun, Chao et al., Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing, Clinical Infectious Diseases

Defelice, The nutraceutical revolution: its impact on food industry R&D, Trends in Food Science & Technology

Doan, Lakhman, Boje, Blood-brain barrier transport studies of organic guanidino cations using an in situ brain perfusion technique, Brain Research

Drouin, Godin, Pagé, The genetics of vitamin C loss in vertebrates, Current Genomics

Erickson, Rhea, Knopp, Banks, Interactions of SARS-CoV-2 with the Blood-Brain Barrier, International Journal of Molecular Sciences

Feyaerts, Luyten, Vitamin C as prophylaxis and adjunctive medical treatment for COVID-19?, Nutrition

Fiorentino, Coppola, Izzo, Annunziata, Bernardo et al., Effects of adding L-arginine orally to standard therapy in patients with COVID-19: A randomized, double-blind, placebo-controlled, parallel-group trial. Results of the first interim analysis, EClinicalMedicine

Grzegorowska, Lorkowski, Possible Correlations between Atherosclerosis, Acute Coronary Syndromes and COVID-19, Journal of Clinical Medicine

Guan, Ni, Hu, Liang, Ou et al., Clinical Characteristics of Coronavirus Disease 2019 in China, The New England Journal of Medicine

Guarner, Three Emerging Coronaviruses in Two Decades: The Story of SARS, MERS, and Now COVID-19, American Journal of Clinical Pathology

Hazan, Stollman, Bozkurt, Papoutsis, Daniels, Lost microbes of COVID-19: Bifidobacterium, Faecalibacterium depletion and decreased microbiome diversity associated with SARS-CoV-2 infection severity, BMJ Open Gastroenterology

Hill, Cowen, Using combination therapy to thwart drug resistance, Future Microbiology

Hoang, Shaw, Fang, Han, Possible application of high-dose vitamin C in the prevention and therapy of coronavirus infection, Journal of Global Antimicrobial Resistance

Holford, Carr, Jovic, Ali, Whitaker et al., Vitamin C-An Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19, Nutrients

Holford, Carr, Zawari, Vizcaychipi, Vitamin C Intervention for Critical COVID-19: A Pragmatic Review of the Current Level of Evidence, Life

Huang, Wang, Li, Ren, Zhao et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet

Ivarsson, Addgene plasmid #

Izzo, Trimarco, Mone, Aloè, Marzani, Combining L-Arginine with vitamin C improves long-COVID symptoms: The LINCOLN Survey, Pharmacological Research

Jezovnik, Poredos, Oxidative stress and atherosclerosis, European Society of Cardiology

Kneller, Phillips, Neill, Jedrzejczak, Stols et al., Structural plasticity of SARS-CoV-2 3CL M pro active site cavity revealed by room temperature X-ray crystallography, Nature Communications

Kontermann, Dual targeting strategies with bispecific antibodies, Taylor & Francis

Krishnamoorthy, Fakhro, Identification of mutation resistance coldspots for targeting the SARS-CoV2 main protease, IUBMB Life

Li, Wu, Important roles of amino acids in immune responses, The British Journal of Nutrition

Malla, Pandey, Aldama, Feliz, Noda et al., Vitamin C Binds to SARS Coronavirus-2 Main Protease Essential for Viral Replication

Najjar, Najjar, Chong, Pramanik, Kirsch et al., Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports, Journal of Neuroinflammation. 2020;

Sencanski, Perovic, Pajovic, Adzic, Paessler et al., Drug Repurposing for Candidate SARS-CoV-2 Main Protease Inhibitors by a Novel In Silico Method, Molecules

Shu, Yang, He, Effect of ascorbic acid and cysteine hydrochloride on growth of Bifidobacterium bifidum, Advance Journal of Food Science and Technology

Singh, Kumar, Pal, Kumari, Bahadur, L-amino-acids as immunity booster against COVID-19: DFT, molecular docking and MD simulations, Journal of Molecular Structure

Skwarecki, Nowak, Milewska, Amino Acid and Peptide-Based Antiviral Agents, ChemMedChem

Subedi, Tchen, Gaire, Hu, Hu, Adjunctive Nutraceutical Therapies for COVID-19, International Journal of Molecular Sciences

Veljkovic, Glisic, Perovic, Veljkovic, The role of longrange intermolecular interactions in discovery of new drugs, Expert Opinion on Drug Discovery

DOI record: { "DOI": "10.31083/j.fbl2801008", "ISSN": [ "2768-6701" ], "URL": "http://dx.doi.org/10.31083/j.fbl2801008", "author": [ { "affiliation": [], "family": "Đukić", "given": "Ivana", "sequence": "first" }, { "affiliation": [], "family": "Kaličanin", "given": "Nevena", "sequence": "first" }, { "affiliation": [], "family": "Sencanski", "given": "Milan", "sequence": "first" }, { "affiliation": [], "family": "Pajovic", "given": "Snezana B.", "sequence": "first" }, { "affiliation": [], "family": "Milicevic", "given": "Jelena", "sequence": "first" }, { "affiliation": [], "family": "Prljic", "given": "Jelena", "sequence": "first" }, { "affiliation": [], "family": "Paessler", "given": "Slobodan", "sequence": "first" }, { "affiliation": [], "family": "Prodanović", "given": "Radivoje", "sequence": "first" }, { "affiliation": [], "family": "Glisic", "given": "Sanja", "sequence": "first" } ], "container-title": "Frontiers in Bioscience-Landmark", "container-title-short": "Front. Biosci. (Landmark Ed)", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2023, 1, 13 ] ], "date-time": "2023-01-13T09:20:10Z", "timestamp": 1673601610000 }, "deposited": { "date-parts": [ [ 2023, 1, 13 ] ], "date-time": "2023-01-13T09:20:17Z", "timestamp": 1673601617000 }, "indexed": { "date-parts": [ [ 2023, 1, 14 ] ], "date-time": "2023-01-14T06:15:06Z", "timestamp": 1673676906896 }, "is-referenced-by-count": 0, "issue": "1", "issued": { "date-parts": [ [ 2023, 1, 13 ] ] }, "journal-issue": { "issue": "1", "published-print": { "date-parts": [ [ 2023 ] ] } }, "language": "en", "link": [ { "URL": "https://www.imrpress.com/journal/FBL/28/1/10.31083/j.fbl2801008", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "16242", "original-title": [], "page": "8", "prefix": "10.31083", "published": { "date-parts": [ [ 2023, 1, 13 ] ] }, "published-print": { "date-parts": [ [ 2023, 1, 13 ] ] }, "publisher": "IMR Press", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "https://www.imrpress.com/journal/FBL/28/1/10.31083/j.fbl2801008" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "General Immunology and Microbiology", "General Biochemistry, Genetics and Molecular Biology", "General Medicine" ], "subtitle": [], "title": "Inhibition of SARS-CoV-2 Mpro with Vitamin C, L-Arginine and a Vitamin C/L-Arginine Combination", "type": "journal-article", "volume": "28" }

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0