Exploring the Therapeutic Potential of Natural Alkaloids Against Covid-19: A Tripartite Investigation of their Efficacy Through In-vivo, In-vitro and In-silico Models

Abstract

In recent times, the world has been experiencing the worst outbreak of Coronavirus disease 2019 (covid-19), a highly contagious disease which originated in Wuhan, China, and has had a global socioeconomic and health impact. Evidence from folkloric medicine show that the disease caused by coronavirus SARS-COV-2 has been treated traditionally while recent advances in sciences show that many vaccines have been produced, tested, approved and used to prevent the spread and contamination of covid-19, some alongside vaccine boosters. Therefore, as a matter of urgency, there is need to discover especially from natural sources, safer, efficient and little or no side effect drugs which can inhibit covid protein target as well as viral enzyme replication such as 3CLpro and PLpro. This research focuses on alkaloids with possible anti-covid-19 activity. Some of these compounds have demonstrated high in-vitro, and in-silico antiviral activity against the recent covid-19 pandemic. A total of 21 alkaloids, isolated between 2000 and 2020 were investigated and reviewed as possible multi-target drugs for the treatment of this disease. The discovery of drugs for the treatment of this disease should therefore be prioritized to drugs from natural sources. Lead drug molecules could be designed from in vivo studies, clinical trials as well as QSAR (quantitative structure-activity relationship) analyses to effectively develop novel drug candidates to tackle this covid-19 pandemic.

References

1. 1. N. Lo, M. Zhou, X. Dong et al., “Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study,” 6e Lancet, vol. 395, no. 10223, pp. 507–513, 2020.
2. 2. N. Zhu, D. Zhang, W. Wang et al., “A novel coronavirus from patients with pneumonia in China, 2019,” New England Journal of Medicine, vol. 382, no. 8, pp. 727–733, 2020.
3. 3. N. Yamamoto, R. Yang, Y. Yoshinaka et al., “HIV protease inhibitor nelfinavir inhibits replication of SARS-associated coronavirus,” Biochemical and Biophysical Research Communications, vol. 318, no. 3, pp. 719–725, 2004.
4. 4. Chattopadhyay D, Naik TN. Antivirals of ethnomedicinal origin:structureactivity relantionship and scope. Mini Rev Med Chem 2007; 7: 275–301.
5. 5. Vanden DA, Vlietinck AJ, Van Hoof DL. Plant products as Potential antiviral agents. Bull Inst Pasteur 1986; 84:101-147.
6. 6. De Clercq E. Antiviral agents: characteristic activity spectrum depending on the molecular target with which they interact. Adv Virus Res 1993; 42: 1-55.
7. 7. Field A. K, Biron K. K. The end of innocence. Revisited: Resistance of herpes viruses to antiviral drugs. Clin Microbiol Rev 1994; 7:1-13.
8. 8. Severson J. L, Tyring S. K. Relation between herpes simplex viruses and human immunodeficiency virus infections. Arch Dermatol 1999; 135:1393-1397.
9. 9. Khan M. T, Ather A., Thompson K.D., Gambari, R. Extracts and molecules from medicinal plants against herpes simplex viruses. Antiviral Res 2005; 67:107-119.
10. 10. Oku N, Gustafson KR, Cartner LK, Wilson JA, Shigematsu N, Hess S, et al. 2004. Neamphamide A, a new HIV-inhibitory depsipeptide from the Papua New Guinea marine sponge Neamphius huxleyi. J. Nat. Prod. 67, 1407–1411.
11. 11. Khan SA, Zia K, Ashraf S, Uddin R, Ul-Haq Z. Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach. J Biomol Struct Dyn 2020;1-10
12. 12. Sarma P, Shekhar N, Prajapat M, Avti P, Kaur H, Kumar S, et al. Insilico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain). J Biomol Struct Dyn 2020:1-9.
13. 13. L. Szla´ vik, A. Gyuris, J. Mina´ rovits, P. Forgo, J. Molna´ r, and J. Hohmann. (2004). Planta Med. 70, 871.
14. 14. S. Y. Li, C. Chen, H. Q. Zhang, H. Y. Guo, H. Wang, L. Wang, X. Zhang, S. N. Hua, J. Yu, P. G. Xiao, R. S. Li, and X. Tan. (2005). Antiviral Res. 67, 18.
15. 15. H. S¸. G¨ulaçtı Topçu, A. T. G¨ulbahar Ozge, and M. A. Vecdi. 2020.¨ “Natural alkaloids as potential anti-coronaviruse compounds,” Bezmialem Science, vol. 8, pp. 131–139.
16. 16. T. Joshi, H. Pundir, P. Sharma, S. Mathpal, and S. Chandra. (2020). “Predictive modeling by deep learning, virtual screening and molecular dynamics study of natural compounds against SARS-CoV-2 main protease,” Journal of Biomolecular Structure and Dynamics, pp. 1–19.
17. 17. Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., et al. (2020b). Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a- ketoamide inhibitors. Science 368 (6489), 409–412.
18. 18. Khaerunnisa, S., Kurniawan, H., Awaluddin, R., Suhartati, S., and Soetjipto, S. (2020). Potential Inhibitor of COVID-19 Main Protease (Mpro) From Several Medicinal Plant Compounds by Molecular Docking Study. Preprints J. 1–14.
19. 19. Chen, H., and Du, Q. (2020). Potential natural compounds for preventing 2019- nCoV infection. Preprints 1–17.
20. 20. Vilar, S., and Costanzi, S. (2012). “Predicting the biological activities through QSAR analysis and docking-based scoring,” in Membrane Protein Structure and Dynamics. Methods in Molecular Biology. Ed. J. Walker (Totowa: Humana Press), 271–284.
21. 21. G. M. Morris, D. S. Goodsell, R. S. Halliday. “Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function,” Journal of Computational Chemistry, vol. 19, no. 14, pp. 1639–1662, 1998.
22. 22. G. M. Morris, R. Huey, W. Lindstrom. “AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility,” Journal of Computational Chemistry, vol. 30, no. 16, pp. 2785–2791, 2009.
23. 23. C.-W. Yang, Y.-Z. Lee, I.-J. Kang.Identification of phenanthroindolizines and phenanthroquinolizidines as novel potent anti-coronaviral agents for porcine enteropathogenic coronavirus transmissible gastroenteritis virus and human severe acute respiratory syndrome coronavirus. Antiviral Research, vol. 88, no. 2, pp. 160–168, 2010.
24. 24. M. Gendrot, J. Andreani, M. Boxberger. Antimalarial drugs inhibit the replication of SARS- CoV-2: An in vitro evaluation. Travel Medicine and Infectious Disease, vol. 37, Article ID 101873, 2020.
25. 25. D. Roza, R. Selly, R. Munsirwan, and G. Fadhilah. Molecular docking of quinine derivative as inhibitor in Sars-Cov-2. Journal of Physics: Conference Series, vol. 1819, no. 1, Article ID 012053, 2021.
26. 26. J. Peng, T. Lin, W. Wang et al., (2013). “Antiviral alkaloids produced by the mangrove-derived fungus Cladosporium sp. PJX-41,” Journal of Natural Products, vol. 76, no. 6, pp. 1133– 1140.
27. 27. G. A. Gyebi, O. B. Ogunro, A. P. Adegunloye, O. M. Ogunyemi, and S. O. Afolabi. Potential inhibitors of coronavirus 3-chymotrypsin-like protease (3CLpro): an in silico screening of alkaloids and terpenoids from African medicinal plants. Journal of Biomolecular Structure and Dynamics, pp. 1–19, 2020.
28. 28. S. Mohammadi, M. Heidarizadeh, M. Entesari. In silico investigation on the inhibiting role of nicotine/caffeine by blocking the S protein of SARS-CoV-2 versus ACE2 receptor. Microorganisms, vol. 8, no. 10, p. 1600, 2020.
29. 29. R. R. Narkhede, A. V. Pise, R. S. Cheke, and S. D. Shinde. Recognition of natural products as potential inhibitors of COVID-19 main protease (Mpro): in-silico evidences. Natural Products and Bioprospecting, vol. 10, no. 5, pp. 297–306, 2020.
30. 30. E. M. Ismail, S. W. Shantier, M. S. Mohammed, H. H. Musa, W. Osman, and R. A. Mothana. Quinoline and quinazoline alkaloids against COVID-19: an in silico multitarget approach. Journal of Chemistry, vol. 2021, Article ID 3613268, pp. 11, 2021.
31. 31. M. T. J. Quimque, K. I. R. Notarte, R. A. T. Fernandez. Virtual screening-driven drug discovery of SARS-CoV2 enzyme inhibitors targeting viral attachment, replication, post- translational modification and host immunity evasion infection mechanisms,” Journal of Biomolecular Structure and Dynamics, pp. 1–18, 2020.
32. 32. N. Kumar, D. Sood, P. J. van der Spek, H. S. Sharma, and R. Chandra, “Molecular binding mechanism and pharmacology comparative analysis of noscapine for repurposing against SARS-CoV-2 protease,” Journal of Proteome Research, vol. 19, no. 11, pp. 4678–4689, 2020.
33. 33. A. El-Demerdash, A. M. Metwaly, A. Hassan et al., “Comprehensive virtual screening of the antiviral potentialities of marine polycyclic guanidine alkaloids against SARS-CoV-2 (COVID-19),” Biomolecules, vol. 11, no. 3, p. 460, 2021.