Evaluation of the potency of FDA-approved drugs on wild type and mutant SARS-CoV-2 helicase (Nsp13)

Ugurel et al., International Journal of Biological Macromolecules, doi:10.1016/j.ijbiomac.2020.09.138

Nov 2020

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In Silico study reporting that folic acid, cangrelor, fludarabine, and polydatin are potential inhibitors of SARS-CoV-2 Nsp13.

13 preclinical studies support the efficacy of vitamin B9 for COVID-19:

8 In Silico studies Chen, Eskandari, Hosseini, Kumar, Pandya, Pennisi, Serseg, Ugurel

4 In Vitro studies Chen, Moatasim, Pennisi, Zhang

1 In Vivo animal study Zhang

Vitamin B9 has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function EFSA, Galmés, Galmés (B). Vitamin B9 inhibits SARS-CoV-2 In Silico Chen, Eskandari, Hosseini, Kumar, Moatasim, Pandya, Serseg, Ugurel, Zhang, reduces spike protein binding ability Zhang, binds with the spike protein receptor binding domain for alpha and omicron variants Pennisi, inhibits the SARS-CoV-2 nucleocapsid protein Chen, inhibits 3CLpro and PLpro in enzymatic assays Pennisi, significantly reduces infection for alpha and omicron SARS-CoV-2 pseudoviruses Pennisi, and inhibits ACE2 expression and SARS-CoV-2 infection in a mouse model Zhang.

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1. Chen et al., Folic acid: a potential inhibitor against SARS-CoV-2 nucleocapsid protein, Pharmaceutical Biology, doi:10.1080/13880209.2022.2063341.tandfonline.com, doi.org.

2. EFSA, Scientific Opinion on the substantiation of health claims related to folate and blood formation (ID 79), homocysteine metabolism (ID 80), energy-yielding metabolism (ID 90), function of the immune system (ID 91), function of blood vessels (ID 94, 175, 192), cell division (ID 193), and maternal tissue growth during pregnancy (ID 2882) pursuant to Article 13(1) of Regulation (EC) No 1924/2006, EFSA Journal, doi:10.2903/j.efsa.2009.1213.europa.eu, doi.org.

3. Eskandari, V., Repurposing the natural compounds as potential therapeutic agents for COVID-19 based on the molecular docking study of the main protease and the receptor-binding domain of spike protein, Journal of Molecular Modeling, doi:10.1007/s00894-022-05138-3.springer.com, doi.org.

4. 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.

5. 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.

6. Hosseini et al., Computational molecular docking and virtual screening revealed promising SARS-CoV-2 drugs, Precision Clinical Medicine, doi:10.1093/pcmedi/pbab001.oup.com, 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. 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.

9. 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.

10. Pennisi et al., An Integrated In Silico and In Vitro Approach for the Identification of Natural Products Active against SARS-CoV-2, Biomolecules, doi:10.3390/biom14010043.mdpi.com, doi.org.

11. Serseg et al., Hispidin and Lepidine E: Two Natural Compounds and Folic Acid as Potential Inhibitors of 2019-novel Coronavirus Main Protease (2019-nCoVMpro), Molecular Docking and SAR Study, Current Computer-Aided Drug Design, doi:10.2174/1573409916666200422075440.eurekaselect.com, doi.org.

12. Ugurel et al., Evaluation of the potency of FDA-approved drugs on wild type and mutant SARS-CoV-2 helicase (Nsp13), International Journal of Biological Macromolecules, doi:10.1016/j.ijbiomac.2020.09.138.sciencedirect.com, doi.org.

13. Zhang et al., Folic acid restricts SARS-CoV-2 invasion by methylating ACE2, Frontiers in Microbiology, doi:10.3389/fmicb.2022.980903.frontiersin.org, doi.org.

Ugurel et al., 30 Nov 2020, peer-reviewed, 8 authors. Contact: dilekbalik@gmail.com, dbalik@yildiz.edu.tr.

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

This Paper Vitamin B9 All

Evaluation of the potency of FDA-approved drugs on wild type and mutant SARS-CoV-2 helicase (Nsp13)

Osman Mutluhan Ugurel, Ozal Mutlu, Emrah Sariyer, Sinem Kocer, Erennur Ugurel, Tugba Gul Inci, Oguz Ata, Dilek Turgut-Balik

International Journal of Biological Macromolecules, doi:10.1016/j.ijbiomac.2020.09.138

SARS-CoV-2 has caused COVID-19 outbreak with nearly 2 M infected people and over 100K death worldwide, until middle of April 2020. There is no confirmed drug for the treatment of COVID-19 yet. As the disease spread fast and threaten human life, repositioning of FDA approved drugs may provide fast options for treatment. In this aspect, structure-based drug design could be applied as a powerful approach in distinguishing the viral drug target regions from the host. Evaluation of variations in SARS-CoV-2 genome may ease finding specific drug targets in the viral genome. In this study, 3458 SARS-CoV-2 genome sequences isolated from all around the world were analyzed. Incidence of C17747T and A17858G mutations were observed to be much higher than others and they were on Nsp13, a vital enzyme of SARS-CoV-2. Effect of these mutations was evaluated on protein-drug interactions using in silico methods. The most potent drugs were found to interact with the key and neighbor residues of the active site responsible from ATP hydrolysis. As result, cangrelor, fludarabine, folic acid and polydatin were determined to be the most potent drugs which have potency to inhibit both the wild type and mutant SARS-CoV-2 helicase. Clinical data supporting these findings would be important towards overcoming COVID-19.

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