Suramin Disturbs the Association of the N-Terminal Domain of SARS-CoV-2 Nucleocapsid Protein with RNA

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2023 Mar 29

PMID 36985506

Authors

Chenyun Guo

Hao Xu

Xiao Li

Jiaxin Yu

Donghai Lin

Affiliations

Soon will be listed here.

Abstract

Suramin was originally used as an antiparasitic drug in clinics. Here, we demonstrate that suramin can bind to the N-terminal domain of SARS-CoV-2 nucleocapsid protein (N-NTD) and disturb its interaction with RNA. The BLI experiments showed that N-NTD interacts suramin with a dissociate constant (K = 2.74 μM) stronger than that of N-NTD with ssRNA-16 (K = 8.37 μM). Furthermore, both NMR titration experiments and molecular docking analysis suggested that suramin mainly binds to the positively charged cavity between the finger and the palm subdomains of N-NTD, and residues R88, R92, R93, I94, R95, K102 and A156 are crucial for N-NTD capturing suramin. Besides, NMR dynamics experiments showed that suramin-bound N-NTD adopts a more rigid structure, and the loop between β2-β3 exhibits fast motion on the ps-ns timescale, potentially facilitating suramin binding. Our findings not only reveal the molecular basis of suramin disturbing the association of SARS-CoV-2 N-NTD with RNA but also provide valuable structural information for the development of drugs against SARS-CoV-2.

Citing Articles

Interference of small compounds and Mg with dsRNA-binding fluorophores compromises the identification of SARS-CoV-2 RdRp inhibitors.

Llanos S, Di Geronimo B, Casajus E, Blanco-Romero E, Fernandez-Leiro R, Mendez J Sci Rep. 2024; 14(1):28250.

PMID: 39548173 PMC: 11568178. DOI: 10.1038/s41598-024-78354-x.

References

Morgan H, McNae I, Nowicki M, Zhong W, Michels P, Auld D . The trypanocidal drug suramin and other trypan blue mimetics are inhibitors of pyruvate kinases and bind to the adenosine site. J Biol Chem. 2011; 286(36):31232-40. PMC: 3173065. DOI: 10.1074/jbc.M110.212613. View

Wu C, Qavi A, Hachim A, Kavian N, Cole A, Moyle A . Characterization of SARS-CoV-2 nucleocapsid protein reveals multiple functional consequences of the C-terminal domain. iScience. 2021; 24(6):102681. PMC: 8168301. DOI: 10.1016/j.isci.2021.102681. View

HAWKING F . Suramin: with special reference to onchocerciasis. Adv Pharmacol Chemother. 1978; 15:289-322. DOI: 10.1016/s1054-3589(08)60486-x. View

Ma J, Zhu F, Zhao M, Shao F, Yu D, Ma J . SARS-CoV-2 nucleocapsid suppresses host pyroptosis by blocking Gasdermin D cleavage. EMBO J. 2021; 40(18):e108249. PMC: 8420271. DOI: 10.15252/embj.2021108249. View

Stohlman S, Baric R, Nelson G, Soe L, Welter L, Deans R . Specific interaction between coronavirus leader RNA and nucleocapsid protein. J Virol. 1988; 62(11):4288-95. PMC: 253863. DOI: 10.1128/JVI.62.11.4288-4295.1988. View

Spyracopoulos L . A suite of Mathematica notebooks for the analysis of protein main chain 15N NMR relaxation data. J Biomol NMR. 2006; 36(4):215-24. DOI: 10.1007/s10858-006-9083-0. View

Chang C, Hou M, Chang C, Hsiao C, Huang T . The SARS coronavirus nucleocapsid protein--forms and functions. Antiviral Res. 2014; 103:39-50. PMC: 7113676. DOI: 10.1016/j.antiviral.2013.12.009. View

Zhang R, Wei D, Du Q, Chou K . Molecular modeling studies of peptide drug candidates against SARS. Med Chem. 2006; 2(3):309-14. DOI: 10.2174/157340606776930736. View

Huang Q, Yu L, Petros A, Gunasekera A, Liu Z, Xu N . Structure of the N-terminal RNA-binding domain of the SARS CoV nucleocapsid protein. Biochemistry. 2004; 43(20):6059-63. DOI: 10.1021/bi036155b. View

10.

Redzic J, Lee E, Born A, Issaian A, Henen M, Nichols P . The Inherent Dynamics and Interaction Sites of the SARS-CoV-2 Nucleocapsid N-Terminal Region. J Mol Biol. 2021; 433(15):167108. PMC: 8214912. DOI: 10.1016/j.jmb.2021.167108. View

11.

Wei D, Zhang R, Du Q, Gao W, Li Y, Gao H . Anti-SARS drug screening by molecular docking. Amino Acids. 2006; 31(1):73-80. PMC: 7087968. DOI: 10.1007/s00726-006-0361-7. View

12.

Jia Z, Liu C, Chen Y, Jiang H, Wang Z, Yao J . Crystal structures of the SARS-CoV-2 nucleocapsid protein C-terminal domain and development of nucleocapsid-targeting nanobodies. FEBS J. 2021; 289(13):3813-3825. PMC: 8646419. DOI: 10.1111/febs.16239. View

13.

Du L, Zhao G, Lin Y, Chan C, He Y, Jiang S . Priming with rAAV encoding RBD of SARS-CoV S protein and boosting with RBD-specific peptides for T cell epitopes elevated humoral and cellular immune responses against SARS-CoV infection. Vaccine. 2008; 26(13):1644-51. PMC: 2600875. DOI: 10.1016/j.vaccine.2008.01.025. View

14.

Yin W, Luan X, Li Z, Zhou Z, Wang Q, Gao M . Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin. Nat Struct Mol Biol. 2021; 28(3):319-325. DOI: 10.1038/s41594-021-00570-0. View

15.

Khan M, Irfan M, Ahsan H, Ahmed A, Kaushik A, Khan A . Structures of SARS-CoV-2 RNA-Binding Proteins and Therapeutic Targets. Intervirology. 2021; 64(2):55-68. PMC: 7900486. DOI: 10.1159/000513686. View

16.

McBride R, Van Zyl M, Fielding B . The coronavirus nucleocapsid is a multifunctional protein. Viruses. 2014; 6(8):2991-3018. PMC: 4147684. DOI: 10.3390/v6082991. View

17.

Cong Y, Ulasli M, Schepers H, Mauthe M, Vkovski P, Kriegenburg F . Nucleocapsid Protein Recruitment to Replication-Transcription Complexes Plays a Crucial Role in Coronaviral Life Cycle. J Virol. 2019; 94(4). PMC: 6997762. DOI: 10.1128/JVI.01925-19. View

18.

Surjit M, Liu B, Chow V, Lal S . The nucleocapsid protein of severe acute respiratory syndrome-coronavirus inhibits the activity of cyclin-cyclin-dependent kinase complex and blocks S phase progression in mammalian cells. J Biol Chem. 2006; 281(16):10669-81. PMC: 7995956. DOI: 10.1074/jbc.M509233200. View

19.

Farrow N, Zhang O, Szabo A, Torchia D, Kay L . Spectral density function mapping using 15N relaxation data exclusively. J Biomol NMR. 1995; 6(2):153-62. DOI: 10.1007/BF00211779. View

20.

Eberle R, Olivier D, Amaral M, Gering I, Willbold D, Arni R . The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CL In Vitro. Viruses. 2021; 13(5). PMC: 8170883. DOI: 10.3390/v13050873. View