Vitamin C inhibits SARS coronavirus-2 main protease essential for viral replication

Malla et al., bioRxiv, doi:10.1101/2021.05.02.442358, May 2021

Source

PDF

All
Studies

Meta
Analysis

https://c19early.org/malla.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 SIlico and In Vitro study showing that vitamin C inhibits SARS-CoV-2 3CL^pro. Authors note that the different clinical results may be explained in part by the widely varying dosages used, and they conclude that vitamin C and/or derivatives may become an important treatment for COVID-19 and other viral infections.

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.

Malla et al., 3 May 2021, preprint, 9 authors.

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

This Paper Vitamin C All

Vitamin C Binds to SARS Coronavirus-2 Main Protease Essential for Viral Replication

Tek Narsingh Malla, Suraj Pandey, Luis Aldama, Dennisse Feliz, Moraima Noda, Ishwor Poudyal, George N Phillips Jr, Emina A Stojković, Marius Schmidt

doi:10.1101/2021.05.02.442358

There is an urgent need for anti-viral agents that treat and/or prevent Covid-19 caused by SARS-Coronavirus (CoV-2) infections. The replication of the SARS CoV-2 is dependent on the activity of two cysteine proteases, a papain-like protease, PL-pro, and the 3C-like protease known as main protease Mpro or 3CLpro. The shortest and the safest path to clinical use is the repurposing of drugs with binding affinity to PLpro or 3CLpro that have an established safety profile in humans. Several studies have reported crystal structures of SARS-CoV-2 main protease in complex with FDA approved drugs such as those used in treatment of hepatitis C. Here, we report the crystal structure of 3CLpro in complex Vitamin C (L-ascorbate) bound to the protein's active site at 2.5 Ångstrom resolution. The crystal structure of the Vitamin C 3CLpro complex may aid future studies on the effect of Vitamin C not only on the coronavirus main protease but on related proteases of other infectious viruses.

Supplementary Material Expression. The CoV-2 3CLpro sequence was synthetized (GenScript) for optimized expression in E. coli according to sequence information published previously (Zhang, Lin, Sun, et al., 2020) . In short, the N-terminus of 3CLpro is fused to glutathione-S-transferase (GST). It further has a 6-His tag at the c-terminus. The N-terminal GST will be autocatalytically cleaved off after expression due to an engineered 3CLpro cleavage sequence. Although the His tag can be cleaved off by a PreScission protease, the tag did not interfere with crystallization and consequently was left on. Overexpression and protein purification protocols were modified from previous reports. E. coli were grown to 0.8 OD 600 at 37 o in terrific broth. Expression was induced by 1 mmol/L IPTG at 25 o C. After 3 h of expression, the culture was induced a second time (1 mmol/L IPTG), and shaken overnight at 20 o C. The yield is about 80 mg for a 6 L culture. Cells were resuspended in lysis buffer (20mM Tris Base, 150 mmol/L NaCl, pH 7.8.). After lysis of the bacterial cells, debris was centrifuged at 50,000 g for 1 hour. The lysate was let stand at room temperature for 3 h (overnight is also possible). After this, the lysate was pumped through a column containing 15 mL of Talon Cobalt resin (TAKARA). The resin was washed without using imidazole using a wash cycle consisting of low salt (20 mmol/L Tris Base, 50 mmol/L NaCl, pH 7.8), high salt (20 mmol/L Tris Base, 1 mol/L NaCl, pH 7.8) and..

References

Adams, Afonine, Bunkoczi, Chen, Davis et al., PHENIX: a comprehensive Python-based system for macromolecular structure solution, Acta Crystallogr D Biol Crystallogr, doi:10.1107/S0907444909052925

Banic, Colunga Biancatelli, Berrill, Marik, Prevention of Rabies by Vitamin C. Nature, Expert Rev Anti Infect Ther, doi:10.1080/14787210.2020

Cui, Li, Shi, Origin and evolution of pathogenic coronaviruses, Nature Reviews Microbiology, doi:10.1038/s41579-018-0118-9

Douangamath, Fearon, Gehrtz, Krojer, Lukacik et al., Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease, Nature Communications, doi:10.1038/s41467-020-18709-w

Fowler Iii, Kim, Lepler, Malhotra, Debesa et al., Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome, World J Crit Care Med, doi:10.5492/wjccm.v6.i1.85

Furuya, Uozaki, Yamasaki, Arakawa, Arita et al., Antiviral effects of ascorbic and dehydroascorbic acids in vitro, Int J Mol Med

Gunther, Reinke, Fernandez-Garcia, Lieske, Lane et al., X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease, Science, doi:10.1126/science.abf7945

Harakeh, Jariwalla, Pauling, Suppression of Human-Immunodeficiency-Virus Replication by Ascorbate in Chronically and Acutely Infected-Cells, Proc Natl Acad Sci U S A, doi:10.1073/pnas.87

Hilgenfeld, From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design, Febs Journal, doi:10.1111/febs.12936

Hoog, Smith, Qiu, Janson, Hellmig et al., Active site cavity of herpesvirus proteases revealed by the crystal structure of herpes simplex virus protease/inhibitor complex, Biochemistry, doi:10.1021/bi9712697

Klein, The Mechanism of the Virucidal Action of Ascorbic Acid, Science, doi:10.1126/science.101.2632.587

Kneller, Galanie, Phillips, O'neill, Coates et al., Malleability of the SARS-CoV-2 3CL M(pro) Active-Site Cavity Facilitates Binding of Clinical Antivirals, Structure, doi:10.1016/j.str.2020.10.007

Liebschner, Afonine, Moriarty, Poon, Sobolev et al., Polder maps: improving OMIT maps by excluding bulk solvent, Acta Crystallogr D Struct Biol, doi:10.1107/S2059798316018210

Mescic Macan, Gazivoda Kraljevic, Raic-Malic, Therapeutic Perspective of Vitamin C and Its Derivatives, Antioxidants, doi:10.3390/antiox8080247

Minor, Cymborowski, Otwinowski, Chruszcz, HKL-3000: the integration of data reduction and structure solution -from diffraction images to an initial model in minutes, Acta Crystallographica Section D-Structural Biology

Murshudov, Skubak, Lebedev, Pannu, Steiner et al., REFMAC5 for the refinement of macromolecular crystal structures, Acta Crystallogr D Biol Crystallogr, doi:10.1107/S0907444911001314

Oeffner, Bunkoczi, Mccoy, Read, Improved estimates of coordinate error for molecular replacement, Acta Crystallographica Section D-Biological Crystallography, doi:10.1107/S0907444913023512

Pauling, Vitamin C and the Common Cold

Ramajayam, Tan, Liang, Recent development of 3C and 3CL protease inhibitors for anti-coronavirus and anti-picornavirus drug discovery, Biochem Soc Trans, doi:10.1042/BST0391371

Sharma, Gupta, Fundamentals of Viruses and Their Proteases, Viral Proteases and Their Inhibitors, doi:10.1016/B978-0-12-809712-0.00001-0

Thomas, Patel, Bittel, Wolski, Wang et al., Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial, JAMA Netw Open, doi:10.1001/jamanetworkopen.2021.0369

Wu, Zhao, Yu, Chen, Wang et al., A new coronavirus associated with human respiratory disease in China, Nature, doi:10.1038/s41586-020-2008-3

Zhang, Lin, Kusov, Nian, Ma et al., alpha-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment, Journal of Medicinal Chemistry

Zhang, Lin, Sun, Curth, Drosten et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors, Science

Zhao, Ling, Li, Peng, Huang et al., Beneficial aspects of high dose intravenous vitamin C on patients with COVID-19 pneumonia in severe condition: a retrospective case series study, Annals of Palliative Medicine, doi:10.21037/apm-20-1387

DOI record: { "DOI": "10.1101/2021.05.02.442358", "URL": "http://dx.doi.org/10.1101/2021.05.02.442358", "abstract": "AbstractThere is an urgent need for anti-viral agents that treat and/or prevent Covid-19 caused by SARS-Coronavirus (CoV-2) infections. The replication of the SARS CoV-2 is dependent on the activity of two cysteine proteases, a papain-like protease, PL-pro, and the 3C-like protease known as main protease Mpro or 3CLpro. The shortest and the safest path to clinical use is the repurposing of drugs with binding affinity to PLpro or 3CLpro that have an established safety profile in humans. Several studies have reported crystal structures of SARS-CoV-2 main protease in complex with FDA approved drugs such as those used in treatment of hepatitis C. Here, we report the crystal structure of 3CLpro in complex Vitamin C (L-ascorbate) bound to the protein’s active site at 2.5 Ångstrom resolution. The crystal structure of the Vitamin C 3CLpro complex may aid future studies on the effect of Vitamin C not only on the coronavirus main protease but on related proteases of other infectious viruses.", "accepted": { "date-parts": [ [ 2021, 5, 20 ] ] }, "author": [ { "ORCID": "http://orcid.org/0000-0002-1387-0801", "affiliation": [], "authenticated-orcid": false, "family": "Malla", "given": "Tek Narsingh", "sequence": "first" }, { "ORCID": "http://orcid.org/0000-0002-7097-2185", "affiliation": [], "authenticated-orcid": false, "family": "Pandey", "given": "Suraj", "sequence": "additional" }, { "affiliation": [], "family": "Aldama", "given": "Luis", "sequence": "additional" }, { "affiliation": [], "family": "Feliz", "given": "Dennisse", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-7582-2127", "affiliation": [], "authenticated-orcid": false, "family": "Noda", "given": "Moraima", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-3498-9801", "affiliation": [], "authenticated-orcid": false, "family": "Poudyal", "given": "Ishwor", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-4171-4603", "affiliation": [], "authenticated-orcid": false, "family": "Phillips", "given": "George N.", "sequence": "additional", "suffix": "Jr." }, { "ORCID": "http://orcid.org/0000-0002-4971-5213", "affiliation": [], "authenticated-orcid": false, "family": "Stojković", "given": "Emina A.", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-0962-9468", "affiliation": [], "authenticated-orcid": false, "family": "Schmidt", "given": "Marius", "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2021, 5, 4 ] ], "date-time": "2021-05-04T04:15:10Z", "timestamp": 1620101710000 }, "deposited": { "date-parts": [ [ 2021, 5, 22 ] ], "date-time": "2021-05-22T18:00:23Z", "timestamp": 1621706423000 }, "group-title": "Biophysics", "indexed": { "date-parts": [ [ 2023, 8, 12 ] ], "date-time": "2023-08-12T19:18:10Z", "timestamp": 1691867890334 }, "institution": [ { "name": "bioRxiv" } ], "is-referenced-by-count": 1, "issued": { "date-parts": [ [ 2021, 5, 3 ] ] }, "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1101/2021.05.02.442358", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "246", "original-title": [], "posted": { "date-parts": [ [ 2021, 5, 3 ] ] }, "prefix": "10.1101", "published": { "date-parts": [ [ 2021, 5, 3 ] ] }, "publisher": "Cold Spring Harbor Laboratory", "reference": [ { "DOI": "10.1107/S0907444909052925", "doi-asserted-by": "publisher", "key": "2021052211000682000_2021.05.02.442358v2.1" }, { "article-title": "Prevention of Rabies by Vitamin C", "first-page": "2", "journal-title": "Nature", "key": "2021052211000682000_2021.05.02.442358v2.2", "volume": "258", "year": "1975" }, { "DOI": "10.1080/14787210.2020.1706483", "article-title": "The antiviral properties of vitamin C", "doi-asserted-by": "crossref", "first-page": "99", "issue": "2", "journal-title": "Expert Rev Anti Infect Ther", "key": "2021052211000682000_2021.05.02.442358v2.3", "volume": "18", "year": "2020" }, { "DOI": "10.1038/s41579-018-0118-9", "doi-asserted-by": "publisher", "key": "2021052211000682000_2021.05.02.442358v2.4" }, { "DOI": "10.1038/s41467-020-18709-w", "article-title": "Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease", "doi-asserted-by": "crossref", "first-page": "5047", "issue": "1", "journal-title": "Nature Communications", "key": "2021052211000682000_2021.05.02.442358v2.5", "volume": "11", "year": "2020" }, { "DOI": "10.5492/wjccm.v6.i1.85", "article-title": "Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome", "doi-asserted-by": "crossref", "first-page": "85", "issue": "1", "journal-title": "World J Crit Care Med", "key": "2021052211000682000_2021.05.02.442358v2.6", "volume": "6", "year": "2017" }, { "article-title": "Antiviral effects of ascorbic and dehydroascorbic acids in vitro", "first-page": "541", "issue": "4", "journal-title": "Int J Mol Med", "key": "2021052211000682000_2021.05.02.442358v2.7", "volume": "22", "year": "2008" }, { "DOI": "10.1126/science.abf7945", "doi-asserted-by": "crossref", "key": "2021052211000682000_2021.05.02.442358v2.8", "unstructured": "Gunther, S. , Reinke, P. Y. A. , Fernandez-Garcia, Y. , Lieske, J. , Lane, T. J. , Ginn, H. M. , Koua, H. M. , Ehrt, C. , Ewert, W. , Oberthuer, D. , Yefanov, O. , Meier, S. , Lorenzen, K. , Krichel, B. , Kopicki, J. D. , Gelisio, L. , Brehm, W. , Dunkel, I. , Seychell, B. , Gieseler, H. , Norton-Baker, B. , Escudero-Perez, B. , Domaracky, M. , Saouane, S. , Tolstikova, A. , White, T. A. , Hanle, A. , Groessler, M. , Fleckenstein, H. , Trost, F. , Galchenkova, M. , Gevorkov, Y. , Li, C. , Awel, S. , Peck, A. , Barthelmess, M. , Schluenzen, F. , Lourdu Xavier, P. , Werner, N. , Andaleeb, H. , Ullah, N. , Falke, S. , Srinivasan, V. , Franca, B. A. , Schwinzer, M. , Brognaro, H. , Rogers, C. , Melo, D. , Zaitseva-Doyle, J. J. , Knoska, J. , Pena-Murillo, G. E. , Mashhour, A. R. , Hennicke, V. , Fischer, P. , Hakanpaa, J. , Meyer, J. , Gribbon, P. , Ellinger, B. , Kuzikov, M. , Wolf, M. , Beccari, A. R. , Bourenkov, G. , von Stetten, D. , Pompidor, G. , Bento, I. , Panneerselvam, S. , Karpics, I. , Schneider, T. R. , Garcia-Alai, M. M. , Niebling, S. , Gunther, C. , Schmidt, C. , Schubert, R. , Han, H. , Boger, J. , Monteiro, D. C. F. , Zhang, L. , Sun, X. , Pletzer-Zelgert, J. , Wollenhaupt, J. , Feiler, C. G. , Weiss, M. S. , Schulz, E. C. , Mehrabi, P. , Karnicar, K. , Usenik, A. , Loboda, J. , Tidow, H. , Chari, A. , Hilgenfeld, R. , Uetrecht, C. , Cox, R. , Zaliani, A. , Beck, T. , Rarey, M. , Gunther, S. , Turk, D. , Hinrichs, W. , Chapman, H. N. , Pearson, A. R. , Betzel, C. , & Meents, A. (2021). X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science. https://doi.org/10.1126/science.abf7945" }, { "DOI": "10.1073/pnas.87.18.7245", "doi-asserted-by": "publisher", "key": "2021052211000682000_2021.05.02.442358v2.9" }, { "DOI": "10.1111/febs.12936", "article-title": "From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design", "doi-asserted-by": "crossref", "first-page": "4085", "issue": "18", "journal-title": "Febs Journal", "key": "2021052211000682000_2021.05.02.442358v2.10", "volume": "281", "year": "2014" }, { "DOI": "10.1021/bi9712697", "doi-asserted-by": "publisher", "key": "2021052211000682000_2021.05.02.442358v2.11" }, { "DOI": "10.1126/science.101.2632.587", "doi-asserted-by": "publisher", "key": "2021052211000682000_2021.05.02.442358v2.12" }, { "DOI": "10.1016/j.str.2020.10.007", "article-title": "Malleability of the SARS-CoV-2 3CL M(pro) Active-Site Cavity Facilitates Binding of Clinical Antivirals", "doi-asserted-by": "crossref", "first-page": "1313", "issue": "12", "journal-title": "Structure", "key": "2021052211000682000_2021.05.02.442358v2.13", "volume": "28", "year": "2020" }, { "DOI": "10.1107/S2059798316018210", "doi-asserted-by": "publisher", "key": "2021052211000682000_2021.05.02.442358v2.14" }, { "DOI": "10.3390/antiox8080247", "doi-asserted-by": "crossref", "key": "2021052211000682000_2021.05.02.442358v2.15", "unstructured": "Mescic Macan, A. , Gazivoda Kraljevic, T. , & Raic-Malic, S. (2019). Therapeutic Perspective of Vitamin C and Its Derivatives. Antioxidants (Basel), 8(8). https://doi.org/10.3390/antiox8080247" }, { "DOI": "10.1107/S0907444906019949", "article-title": "HKL-3000: the integration of data reduction and structure solution - from diffraction images to an initial model in minutes", "doi-asserted-by": "crossref", "first-page": "859", "journal-title": "Acta Crystallographica Section D-Structural Biology", "key": "2021052211000682000_2021.05.02.442358v2.16", "volume": "62", "year": "2006" }, { "DOI": "10.1107/S0907444911001314", "doi-asserted-by": "publisher", "key": "2021052211000682000_2021.05.02.442358v2.17" }, { "DOI": "10.1107/S0907444913023512", "article-title": "Improved estimates of coordinate error for molecular replacement", "doi-asserted-by": "crossref", "first-page": "2209", "journal-title": "Acta Crystallographica Section D-Biological Crystallography", "key": "2021052211000682000_2021.05.02.442358v2.18", "volume": "69", "year": "2013" }, { "key": "2021052211000682000_2021.05.02.442358v2.19", "unstructured": "Pauling, L. (1970). Vitamin C and the Common Cold. W. H. Freeman and Company." }, { "DOI": "10.1042/BST0391371", "doi-asserted-by": "publisher", "key": "2021052211000682000_2021.05.02.442358v2.20" }, { "DOI": "10.1016/B978-0-12-809712-0.00001-0", "doi-asserted-by": "crossref", "key": "2021052211000682000_2021.05.02.442358v2.21", "unstructured": "Sharma, A. , & Gupta, S. P. (2017). Fundamentals of Viruses and Their Proteases. Viral Proteases and Their Inhibitors, 1–24. https://doi.org/10.1016/B978-0-12-809712-0.00001-0" }, { "DOI": "10.1001/jamanetworkopen.2021.0369", "article-title": "Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial", "doi-asserted-by": "crossref", "first-page": "e210369", "issue": "2", "journal-title": "JAMA Netw Open", "key": "2021052211000682000_2021.05.02.442358v2.22", "volume": "4", "year": "2021" }, { "article-title": "A new coronavirus associated with human respiratory disease in China", "first-page": "4", "journal-title": "Nature", "key": "2021052211000682000_2021.05.02.442358v2.23", "volume": "579", "year": "2020" }, { "DOI": "10.1021/acs.jmedchem.9b01828", "article-title": "alpha-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment", "doi-asserted-by": "crossref", "first-page": "4562", "issue": "9", "journal-title": "Journal of Medicinal Chemistry", "key": "2021052211000682000_2021.05.02.442358v2.24", "volume": "63", "year": "2020" }, { "DOI": "10.1126/science.abb3405", "doi-asserted-by": "publisher", "key": "2021052211000682000_2021.05.02.442358v2.25" }, { "DOI": "10.21037/apm-20-1387", "article-title": "Beneficial aspects of high dose intravenous vitamin C on patients with COVID-19 pneumonia in severe condition: a retrospective case series study", "doi-asserted-by": "crossref", "first-page": "1599", "issue": "2", "journal-title": "Annals of Palliative Medicine", "key": "2021052211000682000_2021.05.02.442358v2.26", "volume": "10", "year": "2021" } ], "reference-count": 26, "references-count": 26, "relation": {}, "resource": { "primary": { "URL": "http://biorxiv.org/lookup/doi/10.1101/2021.05.02.442358" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "subtype": "preprint", "title": "Vitamin C Binds to SARS Coronavirus-2 Main Protease Essential for Viral Replication", "type": "posted-content" }

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