Phytochemical Inhibitors of SARS‐CoV‐2 Entry: Targeting the ACE2‐RBD Interaction with l‐Tartaric Acid, l‐Ascorbic Acid, and Curcuma longa Extract
et al., ChemistrySelect, doi:10.1002/slct.202406035, Apr 2025
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.
No treatment is 100% effective. Protocols
combine treatments.
6,300+ studies for
210+ treatments. c19early.org
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In vitro and in silico study showing that l-tartaric acid, l-ascorbic acid, and Curcuma longa extract (curcumin, demethoxycurcumin, bisdemethoxycurcumin) inhibit the SARS-CoV-2 spike RBD interaction with human ACE2. Authors demonstrate by competitive ELISA that l-tartaric acid is most potent (IC₅₀ ≈ 0.009 mg mL⁻¹), l-ascorbic acid reaches half-maximal inhibition at ≈ 0.213 mg mL⁻¹, while C. longa extract shows dose-dependent blockade with IC₅₀ ≈ 0.779 mg mL⁻¹. Molecular docking and 100 ns MD simulations reveal stable hydrogen-bond and hydrophobic networks with ACE2.
17 preclinical studies support the efficacy of vitamin C for COVID-19:
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 function15-17.
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 3CLpro7,11, inhibits SARS-CoV-2 infection by reducing ACE2 levels in a dose-dependent manner12, 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 pathways9.
Vitamin C reduces inflammation, oxidative stress, and NETosis, supporting immune function and vascular protection18.
Intracellular levels of vitamin C decline during COVID-19 hospitalization suggesting ongoing utilization and depletion of vitamin C19.
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 C20.
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 functioning21,22.
Study covers curcumin and vitamin C.
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.
2.
Rajamanickam et al., Exploring the Potential of Siddha Formulation MilagaiKudineer-Derived Phytotherapeutics Against SARS-CoV-2: An In-Silico Investigation for Antiviral Intervention, Journal of Pharmacy and Pharmacology Research, doi:10.26502/fjppr.0105.
3.
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.
4.
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.
5.
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.
6.
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.
7.
Malla et al., Vitamin C inhibits SARS coronavirus-2 main protease essential for viral replication, bioRxiv, doi:10.1101/2021.05.02.442358.
8.
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.
9.
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.
10.
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.
11.
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.
12.
Zuo et al., Vitamin C promotes ACE2 degradation and protects against SARS‐CoV‐2 infection, EMBO reports, doi:10.15252/embr.202256374.
13.
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.
14.
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.
15.
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.
16.
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.
17.
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.
18.
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.
19.
Boerenkamp et al., Low Levels of Serum and Intracellular Vitamin C in Hospitalized COVID-19 Patients, Nutrients, doi:10.3390/nu15163653.
20.
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.
Najimi et al., 28 Apr 2025, peer-reviewed, 10 authors.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
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"abstract": "<jats:title>Abstract</jats:title><jats:p>Phytochemicals are emerging as promising antiviral agents with the potential to address both acute and long‐term complications of viral infections such as COVID‐19. SARS‐CoV‐2, the virus responsible for COVID‐19, enters host cells by binding its spike protein's receptor‐binding domain (RBD) to the angiotensin‐converting enzyme‐2 (ACE2) receptor. Inhibiting this interaction may provide new therapeutic approaches. This study aimed to evaluate the inhibitory effects of <jats:italic>Curcuma longa</jats:italic> extract, <jats:sc>l</jats:sc>‐ascorbic acid, and <jats:sc>l</jats:sc>‐tartaric acid on the ACE2‐RBD interaction and to explore their potential as antiviral agents against SARS‐CoV‐2. A competitive ELISA was used to assess the inhibitory activity on the ACE2‐RBD interaction, with <jats:sc>l</jats:sc>‐tartaric acid showing the strongest inhibition (IC50 = 0.009 mg/ml). <jats:italic>C. longa</jats:italic> extract displayed dose‐dependent inhibition, while <jats:sc>l</jats:sc>‐ascorbic acid showed peak inhibition between 0.4 and 1 mg/mL. Molecular docking and 100 ns molecular dynamics simulations confirmed strong and stable interactions involving curcuminoids with ACE2. These findings underscore the potential of these compounds to function as effective SARS‐CoV‐2 entry inhibitors, supporting their further investigation as promising therapeutic candidates.</jats:p>",
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