Simultaneous Inhibition of SARS-CoV-2 Infectivity by a Specific Combination of Plant-derived Compounds



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Submitted Aug 17, 2021
Published Sep 12, 2021
10.24018/ejbio.2021.2.5.258

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SARS-CoV-2 pandemic remains a challenge to human health and economy worldwide. Previously we have shown that a combination of active plant-derived compounds and plant extracts can dose-dependently inhibit binding of RBD-spike protein SARS-CoV-2 to the ACE2 receptor and its expression on human alveolar epithelial cells. Here we use eGFP-luciferase-SARS-CoV-2 spike protein pseudo-virions and SARS-CoV-2-RdRp, to show if the antiviral effectiveness of this combination of plant-derived compounds and plant extracts expands to other important key mechanisms of SARS-CoV-2 infection. Or results revealed that this combination of five plant-derived compounds inhibited the attachment of the SARS-CoV-2 pseudo-typed particles with lung hACE2/A549 cells. In addition, it down-regulated the activity of key enzymes known to be crucial for the entry of the SARS-CoV-2 virus, such as TMPRSS2, furin and cathepsin L, but not their expression at protein level. This combination did not affect ACE2 binding to and ACE2 enzymatic activity, but modestly decrease cellular expression of neuropilin-1 molecule and significantly inhibited activity of viral RdRp. This study demonstrates inhibitory effects of this combination on key cellular mechanisms of SARS-CoV-2 infection. The findings further support the use of plant-derived compounds as effective health measures against SARS-CoV-2-caused infection.

Keywords: ACE2, cathepsin L, furin, NPR-1, SARS-CoV-2, TMPRSS2

References

  1. I. Chakraborty, P. Maity, “COVID-19 outbreak: Migration, effects on society, global environment and prevention.” Sci. Total Environ, vol. 728, 138882, 2020.
     Google Scholar
  2. WHO Coronavirus Disease (COVID-19) Dashboard. Available: https://covid19.who.int/ 2020/11/9.
     Google Scholar
  3. F. Li. “Structure, Function, and Evolution of Coronavirus Spike Proteins.” Annu. Rev. Virol., vol. 3, pp. 237-261, 2016.
     Google Scholar
  4. N. Zhu, D. Zhang, W. Wang, X. Li, B. Yang, J. Song, et al. “China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China 2019.” N. Engl. J. Med., vol. 382, pp. 727-733, 2020.
     Google Scholar
  5. W. Li, M. J. Moore, N. Vasilieva, J. Sui, S. K. Wong, M. A. Berne, et al. “Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus,” Nature, vol. 426, pp. 450-454, 2003.
     Google Scholar
  6. H. Hoffmann, K. Pyrc, L. van der Hoek, M. Geier, B. Berkhout, S. Pohlmann, et al. “Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry.” Proc. Natl. Acad. Sci. USA, vol. 102, pp. 7988–7993, 2005.
     Google Scholar
  7. L. Du, Y. He, Y. Zhou, S. Liu, B. J. Zheng, S. Jiang, et al. “The spike protein of SARS-CoV – a target for vaccine and therapeutic development.” Nat. Rev. Microbiol, vol. 7, pp. 226-236, 2009.
     Google Scholar
  8. L. Du, Y. Yang, Y. Zhou, L. Lu, F. Li., S. Jiang, et al. “MERS-CoV spike protein: a key target for antivirals.” Expert. Opin. Ther. Targets, vol. 21, pp. 131-143., 2017.
     Google Scholar
  9. L. Cantuti-Castelvetri, R. Ojha, L. D. Pedro, M. Djannatian, J. Franz, S. Kuivanen, et al. “Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity.” Science, vol. 370, pp. 856-860, 2020.
     Google Scholar
  10. J. L. Daly, B. Simonetti, K. Klein, K. E. Chen, M. K. Williamson, C. Anton-Plagaro, et al. “Neuropilin-1 is a host factor for SARS-CoV-2 infection.” Science, vol. 370, pp. 861-865, 2020.
     Google Scholar
  11. X. Ou, Y. Liu, X. Lei, P. Li, D. Mi, L. Ren, et al. “Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV.” Nat. Commun., vol. 11, pp. 1620, 2020.
     Google Scholar
  12. M. Hoffmann, H. Kleine-Weber, S. Schroeder, N. Krüger, T. Herrler, S. Erichsen, et al. “SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.” Cell, vol. 16, no. 181, pp. 271–280, 2020.
     Google Scholar
  13. J. A. Jaimes, N. M. André, J. S. Chappie, K. Jean, and J. K. Millet. “Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop.” J. Mol. Biol. vol. 432, no. 10, pp. 3309–3325, 2020.
     Google Scholar
  14. B. J. Bosch, R. van der Zee, C. A. de Haan, and P. J. Rottier. “The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex.” J. Virol. vol. 77, no. 16, pp. 8801-8811, 2003.
     Google Scholar
  15. A. R. Fehr, and S. Perlman. “Coronaviruses: an overview of their replication and pathogenesis.” Methods Mol. Biol. vol. 1282, pp. 1-23, 2015.
     Google Scholar
  16. J. Zhang, X. Rao, Y. Li, Y. Zhu, F. Liu, G. Guo, et al. “High dose vitamin C infusion for the treatment of critically ill COVID-19.” Ann Intensive Care, vol. 11, no. 1, pp. 5, 2021.
     Google Scholar
  17. V. K. Bhardwaj, R. Singh, J. Sharma, V. Rajendran, R. Purohit, and S. Kumar. “Identification of bioactive molecules from tea plant as SARS-CoV-2 main protease inhibitors.” J Biomol Struct Dyn, vol.39, no. 10, pp. 3449-3458, 2021.
     Google Scholar
  18. A. Andreou, S. Trantza, D. Filippou, N. Sipsas, S. Tsiodras. “COVID-19: The Potential Role of Copper and N-acetylcysteine (NAC) in a Combination of Candidate Antiviral Treatments Against SARS-CoV-2.” In vivo 34, suppl. 3, 1567-1588, 2020.
     Google Scholar
  19. L. Chen, C. Hu, M. Hood, X. Zhang, L. Zhang, J. Kan, et al. “A Novel Combination of Vitamin C, Curcumin and Glycyrrhizic Acid Potentially Regulates Immune and Inflammatory Response Associated with Coronavirus Infections: A Perspective from System Biology Analysis.” Nutrients, vol. 12, no. 4, pp. 1193, 2020.
     Google Scholar
  20. V. Ivanov, S. Ivanova, A. Niedzwiecki, and M. Rath. (January 2021). “Effective and safe global public health strategy to fight the COVID-19 pandemic: Specific micronutrient combination inhibits Coronavirus cell-entry receptor (ACE2) expression.” J. Cell. Med. & Nat. Health. [Online].
     Google Scholar
  21. Available:https://jcmnh.org/index.php/2020/07/02/effective-and-safe-global-public-health-strategy-to-fight-the-covid-19-pandemic-specific-micronutrient-composition-inhibits-coronavirus-cell-entry-receptor-ace2-expression/.
     Google Scholar
  22. A. Goc, W. Sumera, V. Ivanov, A. Niedzwiecki, and M. Rath, M. (August 2020) “Micronutrient combination inhibits two key steps of coronavirus (SARS-CoV-2) infection: viral binding to ACE2 receptor and its cellular expression.” J. Cell. Med. & Nat. Health. [Online]. Available:https://jcmnh.org/index.php/2020/08/14/micronutrient-combination-inhibits-two-key-steps-of-coronavirus-sars-cov-2-infection-viral-binding-to-ace2-receptor-and-its-cellular-expression/.
     Google Scholar
  23. R. Pászti-Gere, R. Czimmermann, G. Ujhelyi, P. Balla, A. Maiwald, and T. Steinmetzer. (2016) “In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells.” J. Enzyme Inhib. Med. Chem., vol. 31, suppl. 9, pp. 123-129, 2016.
     Google Scholar
  24. I. Glowacka, S. Bertram, M. A. Müller, P. Allen, E. Soilleux., S. Pfefferle, et al. (2011) “Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response,” J. Virol. vol. 85, no. 9, pp. 4122-4134, 2011.
     Google Scholar
  25. Iwata-Yoshikawa, N., Okamura, T., Shimizu, Y., Hasegawa, H., Takeda, M., et al. (2019) “TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection.” J. Virol. 93, 01815-01818.
     Google Scholar
  26. T. Liu, S. Luo, P. Libby, and G. P. Shi. “Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients.” Pharmacol. Ther. Vol. 213, pp. 107587, 2011.
     Google Scholar
  27. S. Tian, Q. Huang, Y. Fang, J. Wu. “Furin DB: A database of 20-residue furin cleavage site motifs, substrates and their associated drugs.” Int. J. Mol. Sci., vol. 12, no. 2. pp. 1060–1065, 2011.
     Google Scholar
  28. K. E. Follis, J. York, J. H. Nunberg. “Furin cleavage of the SARS coronavirus spike glycoprotein enhances cell-cell fusion but does not affect virion entry.” Virology, vol. 350, no. 2, pp. 358–369. 2006.
     Google Scholar
  29. B. A. Johnson, X. Xie, B. K. Kumari, G. Lokugamage, A. Muruato, A., J. Zou, et al. (2020) “Furin Cleavage Site Is Key to SARS-CoV-2 Pathogenesis.” bioRxiv, [Preprint], Aug 26:2020.08.26.268854, 2020.
     Google Scholar
  30. Y. Ming, and L. Qiang. “Involvement of Spike Protein, Furin, and ACE2 in SARS-CoV-2-Related Cardiovascular Complications.” SN Compr. Clin. Med. [Online ahead of print] vol. 11, 1-6, 2020.
     Google Scholar
  31. E. K. Barbour, E. G. Rayya, A. S. Houssam, R. G. El-Hakim, A. Niedzwiecki, et al. “Alleviation of Histopathologic Effects of Avian Influenza Virus by a Specific Nutrient Synergy.” Int. J. Appl. Res. Vet. Med. vol. 5, pp. 9-16, 2007.
     Google Scholar
  32. P. G. Deryabin, D. K. Lvov, A. G. Botikov, V. Ivanov, T. Kalinovsky, A. Niedzwiecki, et al. “Effects of a nutrient mixture on infectious properties of the highly pathogenic strain of avian influenza virus A/H5N1.” BioFactors, vol. 33, no. 2, pp. 85-97, 2008.
     Google Scholar
  33. R. J. Jariwalla, M. W. Roomi, B. Gangapurkar, T. Kalinovsky, A. Niedzwiecki., M. Rath, “Suppression of influenza A virus nuclear antigen production and neuraminidase activity by a nutrient mixture containing ascorbic acid, green tea extract and amino acids.” BioFactors, vol. 31, no. 1, pp 1-15, 2007.
     Google Scholar
  34. R. J. Jariwalla, B. Gangapurkar, A. Pandit, T. Kalinovsky, A. Niedzwiecki, and M. Rath, “Micronutrient Cooperation in Suppression of HIV Production in Chronically and Latently Infected Cells.” Mol. Med. Rep. vol. 3, no. 3, pp. 377-385, 2010.
     Google Scholar