Omicron variants of SARS CoV-2 indicate how small molecules can interfere with spike glycoprotein trimerization

Neri Niccolai, Alfonso Trezza, Federico Marchini, Pietro Bongini, Monica Bianchini, Annalisa Santucci, Ottavia Spiga, Anna Visibelli

Article ID: 2325
Vol 6, Issue 3, 2023

VIEWS - 655 (Abstract) 62 (PDF)

Abstract


In our search for a possible achilles’ heel of SARS-CoV-2, we explored the variability of 1,382,462 complete sequences of the viral spike glycoprotein, all the ones that we could retrieve from the NCBI SARS-CoV-2 databank as of 6 March 2023. Then, by using the Shannon entropy algorithm, we quantified the sequence variability of SARS-CoV-2 spike glycoprotein. With PDBePISA, we have performed a detailed analysis of protomer-protomer interfaces of the spike glycoprotein for two representative structures of different viral variants. The largest protomer-protomer contact patch that is present in the stem region of both structures is highly conserved. It is remarkable that the Asp796Tyr mutation, centered in this patch, is always present in all the Omicron variants. The structure of the SARS-CoV-2 Omicron spike glycoprotein trimer indicates that Tyr796 and Phe898 of the same protomer form a network of aromatic sidechains with Tyr707 of another protomer, yielding a strong constraint that stabilizes the spike glycoprotein quaternary assembly. We believe that the resulting structural stability of the viral trimer is among the key features for the successful proliferation of Omicron variants. This finding also supports the fact that disrupting this network of aromatic moieties with suitable small molecules would represent a powerful antiviral strategy.


Keywords


SARS-CoV-2; Omicron variants; sequence variability; spike glycoprotein; structure disassembly; interfering ligands

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References


1. Miljanovic D, Cirkovic A, Lazarevic I, et al. Clinical efficacy of anti-SARS-CoV-2 monoclonal antibodies in preventing hospitalisation and mortality among patients infected with Omicron variants: A systematic review and meta-analysis. Reviews in Medical Virology 2023; 33(4): e2439. doi: 10.1002/rmv.2439

2. Zhou Y, Wang H, Yang L, Wang Q. Progress on COVID-19 chemotherapeutics discovery and novel technology. Molecules 2022; 27(23): 8257. doi: 10.3390/molecules27238257

3. Zhan W, Tian X, Zhang X, et al. Structural study of SARS-CoV-2 antibodies identifies a broad-spectrum antibody that neutralizes the omicron variant by disassembling the spike trimer. Journal of Virology 2022; 96(16): e0048022. doi: 10.1128/jvi.00480-22

4. Bongini P, Trezza A, Bianchini M, et al. A possible strategy to fight COVID-19: Interfering with spike glycoprotein trimerization. Biochemical and Biophysical Research Communications 2020; 528(1): 35–38. doi: 10.1016/j.bbrc.2020.04.007

5. Delmas B, Laude H. Assembly of coronavirus spike protein into trimers and its role in epitope expression. Journal of Virology 1990; 64(11): 5367–5375. doi: 10.1128/JVI.64.11.5367-5375

6. Sievers F, Wilm A, Dineen D, et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Molecular Systems Biology 2011; 7: 539. doi: 10.1038/msb.2011.75

7. Bakan A, Dutta A, Mao W, et al. Evol and ProDy for bridging protein sequence evolution and structural dynamics. Bioinformatics 2014; 30(18): 2681–2683. doi: 10.1093/bioinformatics/btu336

8. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367(6483): 1260–1263. doi: 10.1126/science.abb2507

9. Krissinel E, Henrick K. Inference of macromolecular assemblies from crystalline state. Journal of Molecular Biology 2007; 372(3): 774–797. doi: 10.1016/j.jmb.2007.05.022

10. Koebel MR, Schmadeke G, Posner RG, Sirimulla S. AutoDock VinaXB: Implementation of XBSF, new empirical halogen bond scoring function, into AutoDock Vina. Journal of Cheminformatics 2016; 8(1): 27. doi: 10.1186/s13321-016-0139-1

11. Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: A major update to the DrugBank database for 2018. Nucleic Acids Research 2018; 46(D1): D1074–D1082. doi: 10.1093/nar/gkx1037

12. Magazine N, Zhang T, Wu Y, et al. Mutations and evolution of the SARS-CoV-2 spike protein. Viruses 2022; 14(3): 640. doi: 10.3390/v14030640

13. Mistry P, Barmania F, Mellet J, et al. SARS-CoV-2 variants, vaccines, and host immunity. Frontiers in Immunology 2022; 12: 809244. doi: 10.3389/fimmu.2021.809244

14. Alkhatib M, Salpini R, Carioti L, et al. Update on SARS-CoV-2 omicron variant of concern and its peculiar mutational profile. Microbiology Spectrum 2022; 10(2): e0273221. doi: 10.1128/spectrum.02732-21

15. Gurung AB, Ali MA, Lee J, et al. The potential of Paritaprevir and Emetine as inhibitors of SARS-CoV-2 RdRp. Saudi Journal of Biological Sciences 2021; 28(2): 1426–1432. doi: 10.1016/j.sjbs.2020.11.078

16. Kemp SA, Collier DA, Datir RP, et al. Author correction: SARS-CoV-2 evolution during treatment of chronic infection. Nature 2022; 608(7922): E23. doi: 10.1038/s41586-022-05104-2

17. Araf Y, Akter F, Tang YD, et al. Omicron variant of SARS-CoV-2: Genomics, transmissibility, and responses to current COVID-19 vaccines. Journal of Medical Virology 2022; 94(5): 1825–1832. doi: 10.1002/jmv.27588

18. Farheen S, Araf Y, Tang YD, Zheng C. The Deltacron conundrum: Its origin and potential health risks. Journal of Medical Virology 2022; 94(11): 5096–5102. doi: 10.1002/jmv.27990




DOI: https://doi.org/10.24294/ace.v6i3.2325

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