The Structure of Spike Protein in SARS-Cov-2 and its Receptors on Host cell: Strategies for Drug Discovery Based on the Natural Products

Document Type : Analytic Review

Authors
TMU
Abstract
The new Coronavirus, which was named SARS-CoV-2 is one of the members of the Coronavirus family, which induces Covid-19 or acute respiratory infection. This virus was firstly known in 2019 in Wuhan, China; and then, rapidly propagated around the world. In this review, we will present the structure and function of the Spike (S) protein in this virus and its receptors on the host cells. In addition to ACE2, which was initially identified as the cell surface receptor of this virus, it was observed that CD147 and GRP 78 also act as the receptors on host cells. Also, based on the mechanism of action, a brief introduction will present the drugs used to treat this Coronavirus. The drugs that target S protein, Proteinases; RNA-dependent RNA polymerases, helicases, or structural lipids of the virus membrane. In addition, the proposed natural products which are currently recommended as supplements are discussed. For example, flavonoids, polyphenols, and polar compounds are substances whose antiviral effects against Coronavirus have been studied and demonstrated. In conclusion, since the effective drug to eradicate this virus is not yet known, it seems that according to the structural characteristics and mechanism of action, using natural compounds as a complementary or preventive medicine will be useful to inhibit or delay the entrance, proliferation, and/ or infectivity of the virus.

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1. WHO, Q&A on coronaviruses (COVID-19). 2020.
2. Odega, K., et al., Safe Laboratory Practices in the Light of Covid-19 Pandemic: Way Forward in a Resource Limited Setting. 2020.
3. Shereen, M.A., et al., COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses. J Adv Res, 2020. 24: p. 91-98.
4. Han, Y. and P. Kral, Computational Design of ACE2-Based Peptide Inhibitors of SARS-CoV-2. ACS Nano, 2020.
5. Wu, C., et al., Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B, 2020.
6. Anatomy of a killer. Understanding SARS-CoV-2 and the drugs that might lessen its power. 2020; Available from: https://www.economist.com/briefing/2020/03/12/understanding-sars-cov-2-and-the-drugs-that-might-lessen-its-power,.
7. Lu, G., Q. Wang, and G.F. Gao, Bat-to-human: spike features determining 'host jump' of coronaviruses SARS-CoV, MERS-CoV, and beyond. Trends Microbiol, 2015. 23(8): p. 468-78.
8. Beniac, D.R., et al., Conformational reorganization of the SARS coronavirus spike following receptor binding: implications for membrane fusion. PLoS One, 2007. 2(10): p. e1082.
9. Belouzard, S., V.C. Chu, and G.R. Whittaker, Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc Natl Acad Sci U S A, 2009. 106(14): p. 5871-6.
10. Bosch, B.J., et al., The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J Virol, 2003. 77(16): p. 8801-11.
11. Walls, A.C., et al., Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell, 2020. 181(2): p. 281-292 e6.
12. Lan, J., et al., Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature, 2020.
13. Xu, X., et al., Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Science China Life Sciences, 2020. 63(3): p. 457-460.
14. Li, Y., et al., Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor. Pharmacol Res, 2020: p. 104833.
15. Qiu, Y., et al., Predicting the angiotensin converting enzyme 2 (ACE2) utilizing capability as the receptor of SARS-CoV-2. Microbes Infect, 2020.
16. Wang, Q., et al., Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell, 2020.
17. Yan, R., et al., Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science, 2020. 367(6485): p. 1444-1448.
18. Zhang, H., et al., Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med, 2020. 46(4): p. 586-590.
19. Letko, M., A. Marzi, and V. Munster, Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol, 2020. 5(4): p. 562-569.
20. Wrapp, D., et al., Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science, 2020. 367(6483): p. 1260-1263.
21. Hoffmann, M., et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 2020. 181(2): p. 271-280 e8.
22. Shang, J., et al., Structural basis of receptor recognition by SARS-CoV-2. Nature, 2020.
23. Bosch, B.J., et al., Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides. Proc Natl Acad Sci U S A, 2004. 101(22): p. 8455-60.
24. Xia, S., et al., Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res, 2020. 30(4): p. 343-355.
25. Vaarala, M.H., et al., Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues. J Pathol, 2001. 193(1): p. 134-40.
26. Harrison, S.C., Viral membrane fusion. Virology, 2015. 479-480: p. 498-507.
27. Fan, X., et al., Cryo-EM analysis of the post-fusion structure of the SARS-CoV spike glycoprotein. Nat Commun, 2020. 11(1): p. 3618.
28. Wang, K., et al., SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. BioRxiv, 2020.
29. Zou, X., et al., Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med, 2020. 14(2): p. 185-192.
30. Li, M.Y., et al., Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty, 2020. 9(1): p. 45.
31. Su, H. and Y. Yang, The roles of CyPA and CD147 in cardiac remodelling. Experimental and molecular pathology, 2018. 104(3): p. 222-226.
32. Ibrahim, I.M., et al., COVID-19 spike-host cell receptor GRP78 binding site prediction. J Infect, 2020.
33. Kupferschmidt, K. and J. Cohen, Race to find COVID-19 treatments accelerates. Science, 2020. 367(6485): p. 1412-1413.
34. Riggioni, C., et al., A compendium answering 150 questions on COVID-19 and SARS-CoV-2. Allergy, 2020.
35. Du, L., et al., The spike protein of SARS-CoV--a target for vaccine and therapeutic development. Nat Rev Microbiol, 2009. 7(3): p. 226-36.
36. Sui, J., et al., Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc Natl Acad Sci U S A, 2004. 101(8): p. 2536-41.
37. Lip, K.M., et al., Monoclonal antibodies targeting the HR2 domain and the region immediately upstream of the HR2 of the S protein neutralize in vitro infection of severe acute respiratory syndrome coronavirus. J Virol, 2006. 80(2): p. 941-50.
38. Ng, O.W., et al., Substitution at aspartic acid 1128 in the SARS coronavirus spike glycoprotein mediates escape from a S2 domain-targeting neutralizing monoclonal antibody. PLoS One, 2014. 9(7): p. e102415.
39. Coughlin, M.M. and B.S. Prabhakar, Neutralizing human monoclonal antibodies to severe acute respiratory syndrome coronavirus: target, mechanism of action, and therapeutic potential. Rev Med Virol, 2012. 22(1): p. 2-17.
40. Elshabrawy, H.A., et al., Human monoclonal antibodies against highly conserved HR1 and HR2 domains of the SARS-CoV spike protein are more broadly neutralizing. PLoS One, 2012. 7(11): p. e50366.
41. Liu, B. and J. Zhou, SARS-CoV protease inhibitors design using virtual screening method from natural products libraries. J Comput Chem, 2005. 26(5): p. 484-90.
42. Lung, J., et al., The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase. J Med Virol, 2020. 92(6): p. 693-697.
43. Toney, J.H., et al., Sabadinine: a potential non-peptide anti-severe acute-respiratory-syndrome agent identified using structure-aided design. J Med Chem, 2004. 47(5): p. 1079-80.
44. Wang, S.Q., et al., Virtual screening for finding natural inhibitor against cathepsin-L for SARS therapy. Amino Acids, 2007. 33(1): p. 129-35.
45. Zhang, D.H., et al., In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. J Integr Med, 2020. 18(2): p. 152-158.
46. Forli, S., et al., Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat Protoc, 2016. 11(5): p. 905-19.
47. Aldeghi, M., et al., Accurate calculation of the absolute free energy of binding for drug molecules. Chem Sci, 2016. 7(1): p. 207-218.
48. Chen, Y., C. de Bruyn Kops, and J. Kirchmair, Data Resources for the Computer-Guided Discovery of Bioactive Natural Products. J Chem Inf Model, 2017. 57(9): p. 2099-2111.
49. Ul Qamar, M.T., et al., Structural basis of SARS-CoV-2 3CL(pro) and anti-COVID-19 drug discovery from medicinal plants. J Pharm Anal, 2020.
50. Naidoo, D., et al., Cyanobacterial metabolites as promising drug leads against the M(pro) and PL(pro) of SARS-CoV-2: an in silico analysis. J Biomol Struct Dyn, 2020: p. 1-13.
51. Swaim, C.D., et al., 6-Thioguanine blocks SARS-CoV-2 replication by inhibition of PLpro protease activities. bioRxiv, 2020.
52. Rut, W., et al., Activity profiling and structures of inhibitor-bound SARS-CoV-2-PLpro protease provides a framework for anti-COVID-19 drug design. bioRxiv, 2020.
53. Abedi, F., R. Rezaee, and G. Karimi, Plausibility of therapeutic effects of Rho kinase inhibitors against Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19). Pharmacol Res, 2020. 156: p. 104808.
54. Baglivo, M., et al., Natural small molecules as inhibitors of coronavirus lipid-dependent attachment to host cells: a possible strategy for reducing SARS-COV-2 infectivity? Acta Biomed, 2020. 91(1): p. 161-164.
55. Bifulco, M. and P. Gazzerro, Statins in coronavirus outbreak: It's time for experimental and clinical studies. Pharmacol Res, 2020. 156: p. 104803.
56. Hashemi, S.A. and S.Z. Bathaie, The in Silico Mechanism of hVKOR Interaction with Acetaminophen, its Metabolite, and N- Acetyl Cysteine; Caution on Application in COVID-19 Patients. Submitted., 2020.
57. Lung, J., et al., The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase. J Med Virol, 2020.
58. Cassidy, L., et al., Oxidative stress in alzheimer's disease: A review on emergent natural polyphenolic therapeutics. Complement Ther Med, 2020. 49: p. 102294.
59. Khan, H., et al., Polyphenols in the treatment of autoimmune diseases. Autoimmun Rev, 2019. 18(7): p. 647-657.
60. Tome-Carneiro, J. and F. Visioli, Polyphenol-based nutraceuticals for the prevention and treatment of cardiovascular disease: Review of human evidence. Phytomedicine, 2016. 23(11): p. 1145-74.
61. Pandey, P., et al., Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development. J Biomol Struct Dyn, 2020: p. 1-11.
62. Kumar, A., et al., Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches. J Biomol Struct Dyn, 2020: p. 1-11.
63. Li, S.Y., et al., Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res, 2005. 67(1): p. 18-23.
64. Kretzing, S., et al., Dose-dependent emetic effects of the Amaryllidaceous alkaloid lycorine in beagle dogs. Toxicon, 2011. 57(1): p. 117-24.
65. Hakkinen, S.H., et al., Content of the flavonols quercetin, myricetin, and kaempferol in 25 edible berries. J Agric Food Chem, 1999. 47(6): p. 2274-9.
66. Miean, K.H. and S. Mohamed, Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J Agric Food Chem, 2001. 49(6): p. 3106-12.
67. Zhao, Q., X.Y. Chen, and C. Martin, Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants. Sci Bull (Beijing), 2016. 61(18): p. 1391-1398.
68. Park, J.Y., et al., Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors. J Enzyme Inhib Med Chem, 2017. 32(1): p. 504-515.
69. Justesen, U. and P. Knuthsen, Composition of flavonoids in fresh herbs and calculation of flavonoid intake by use of herbs in traditional Danish dishes. Food chemistry, 2001. 73(2): p. 245-250.
70. Kaack, K. and T. Austed, Interaction of vitamin C and flavonoids in elderberry (Sambucus nigra L.) during juice processing. Plant Foods Hum Nutr, 1998. 52(3): p. 187-98.
71. Yu, M.S., et al., Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorg Med Chem Lett, 2012. 22(12): p. 4049-54.
72. Kim, D.W., et al., Phenolic phytochemical displaying SARS-CoV papain-like protease inhibition from the seeds of Psoralea corylifolia. J Enzyme Inhib Med Chem, 2014. 29(1): p. 59-63.
73. Yang, K.S., et al., A Speedy Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors. bioRxiv, 2020.
74. Ghosh, R., et al., Identification of polyphenols from Broussonetia papyrifera as SARS CoV-2 main protease inhibitors using in silico docking and molecular dynamics simulation approaches. J Biomol Struct Dyn, 2020: p. 1-14.
75. Mohammad, T., et al., Identification of high-affinity inhibitors of SARS-CoV-2 main protease: Towards the development of effective COVID-19 therapy. Virus Res, 2020. 288: p. 198102.
76. Fiorucci, D., et al., Computational drug repurposing for the identification of SARS-CoV-2 main protease inhibitors. J Biomol Struct Dyn, 2020: p. 1-7.
77. Bhardwaj, V.K., et al., Identification of bioactive molecules from tea plant as SARS-CoV-2 main protease inhibitors. J Biomol Struct Dyn, 2020: p. 1-10.
78. Mitchell, C.A., K. Ramessar, and B.R. O'Keefe, Antiviral lectins: Selective inhibitors of viral entry. Antiviral Res, 2017. 142: p. 37-54.
79. Hwang, H.J., et al., Characterization of a Novel Mannose-Binding Lectin with Antiviral Activities from Red Alga, Grateloupia chiangii. Biomolecules, 2020. 10(2).
80. Coves-Datson, E.M., et al., Inhibition of Ebola Virus by a Molecularly Engineered Banana Lectin. PLoS Negl Trop Dis, 2019. 13(7): p. e0007595.
81. Michelow, I.C., et al., High-dose mannose-binding lectin therapy for Ebola virus infection. J Infect Dis, 2011. 203(2): p. 175-9.
82. Keyaerts, E., et al., Plant lectins are potent inhibitors of coronaviruses by interfering with two targets in the viral replication cycle. Antiviral Res, 2007. 75(3): p. 179-87.
83. Petersen, K.A., et al., Phase I safety, tolerability, and pharmacokinetic study of recombinant human mannan-binding lectin. J Clin Immunol, 2006. 26(5): p. 465-75.
84. Han, T., et al., Bioactivity-guided fractionation for anti-inflammatory and analgesic properties and constituents of Xanthium strumarium L. Phytomedicine, 2007. 14(12): p. 825-9.
85. Tian, F., et al., Antioxidant and antimicrobial activities of consecutive extracts from Galla chinensis: The polarity affects the bioactivities. Food chemistry, 2009. 113(1): p. 173-179.
86. Wigmore, S.M., M. Naiker, and D.C. Bean, Antimicrobial Activity of Extracts from Native Plants of Temperate Australia. Pharmacognosy Communications, 2016. 6(2).
87. Choi, H.J., et al., Antiviral activity of quercetin 7-rhamnoside against porcine epidemic diarrhea virus. Antiviral Res, 2009. 81(1): p. 77-81.
88. Mani, J.S., et al., Natural product-derived phytochemicals as potential agents against coronaviruses: A review. Virus Res, 2020. 284: p. 197989.
89. O'Keefe, B.R., et al., Broad-spectrum in vitro activity and in vivo efficacy of the antiviral protein griffithsin against emerging viruses of the family Coronaviridae. J Virol, 2010. 84(5): p. 2511-21.
90. Muller, C., et al., Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses. Antiviral Res, 2018. 150: p. 123-129.
91. Zhuang, M., et al., Procyanidins and butanol extract of Cinnamomi Cortex inhibit SARS-CoV infection. Antiviral Res, 2009. 82(1): p. 73-81.
92. Lau, K.M., et al., Immunomodulatory and anti-SARS activities of Houttuynia cordata. J Ethnopharmacol, 2008. 118(1): p. 79-85.