Selective Serotonin Reuptake Inhibitor Fluoxetine Inhibits Replication of Human Enteroviruses B and D by Targeting Viral Protein 2C

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2013 Jan 22

PMID 23335743

Citations 39

Authors

Rachel Ulferts

Lonneke van der Linden

Hendrik Jan Thibaut

Kjerstin H W Lanke

Pieter Leyssen

Bruno Coutard

Armando M De Palma

Bruno Canard

Johan Neyts

Frank J M van Kuppeveld

Affiliations

Soon will be listed here.

Abstract

Although the genus Enterovirus contains many important human pathogens, there is no licensed drug for either the treatment or the prophylaxis of enterovirus infections. We report that fluoxetine (Prozac)--a selective serotonin reuptake inhibitor--inhibits the replication of human enterovirus B (HEV-B) and HEV-D but does not affect the replication of HEV-A and HEV-C or human rhinovirus A or B. We show that fluoxetine interferes with viral RNA replication, and we identified viral protein 2C as the target of this compound.

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References

Teterina N, Gorbalenya A, Egger D, Bienz K, EHRENFELD E . Poliovirus 2C protein determinants of membrane binding and rearrangements in mammalian cells. J Virol. 1997; 71(12):8962-72. PMC: 230196. DOI: 10.1128/JVI.71.12.8962-8972.1997. View

Gorbalenya A, Koonin E, Wolf Y . A new superfamily of putative NTP-binding domains encoded by genomes of small DNA and RNA viruses. FEBS Lett. 1990; 262(1):145-8. DOI: 10.1016/0014-5793(90)80175-i. View

Yin J, Liu Y, Wimmer E, Paul A . Complete protein linkage map between the P2 and P3 non-structural proteins of poliovirus. J Gen Virol. 2007; 88(Pt 8):2259-2267. DOI: 10.1099/vir.0.82795-0. View

Tang W, Yang S, Wu B, Jheng J, Chen Y, Shih C . Reticulon 3 binds the 2C protein of enterovirus 71 and is required for viral replication. J Biol Chem. 2006; 282(8):5888-98. DOI: 10.1074/jbc.M611145200. View

De Palma A, Heggermont W, Lanke K, Coutard B, Bergmann M, Monforte A . The thiazolobenzimidazole TBZE-029 inhibits enterovirus replication by targeting a short region immediately downstream from motif C in the nonstructural protein 2C. J Virol. 2008; 82(10):4720-30. PMC: 2346740. DOI: 10.1128/JVI.01338-07. View

Zuo J, Quinn K, Kye S, Cooper P, Damoiseaux R, Krogstad P . Fluoxetine is a potent inhibitor of coxsackievirus replication. Antimicrob Agents Chemother. 2012; 56(9):4838-44. PMC: 3421851. DOI: 10.1128/AAC.00983-12. View

Hsu N, Ilnytska O, Belov G, Santiana M, Chen Y, Takvorian P . Viral reorganization of the secretory pathway generates distinct organelles for RNA replication. Cell. 2010; 141(5):799-811. PMC: 2982146. DOI: 10.1016/j.cell.2010.03.050. View

Sweeney T, Cisnetto V, Bose D, Bailey M, Wilson J, Zhang X . Foot-and-mouth disease virus 2C is a hexameric AAA+ protein with a coordinated ATP hydrolysis mechanism. J Biol Chem. 2010; 285(32):24347-59. PMC: 2915670. DOI: 10.1074/jbc.M110.129940. View

Adams P, Kandiah E, Effantin G, Steven A, Ehrenfeld E . Poliovirus 2C protein forms homo-oligomeric structures required for ATPase activity. J Biol Chem. 2009; 284(33):22012-22021. PMC: 2755925. DOI: 10.1074/jbc.M109.031807. View

10.

Wessels E, Duijsings D, Notebaart R, Melchers W, van Kuppeveld F . A proline-rich region in the coxsackievirus 3A protein is required for the protein to inhibit endoplasmic reticulum-to-golgi transport. J Virol. 2005; 79(8):5163-73. PMC: 1069528. DOI: 10.1128/JVI.79.8.5163-5173.2005. View

11.

Echeverri A, Banerjee R, Dasgupta A . Amino-terminal region of poliovirus 2C protein is sufficient for membrane binding. Virus Res. 1998; 54(2):217-23. DOI: 10.1016/s0168-1702(98)00016-1. View

12.

Klein M, Hadaschik D, Zimmermann H, Eggers H . The picornavirus replication inhibitors HBB and guanidine in the echovirus-9 system: the significance of viral protein 2C. J Gen Virol. 2000; 81(Pt 4):895-901. DOI: 10.1099/0022-1317-81-4-895. View

13.

LLerena A, Dorado P, Berecz R, Gonzalez A, Norberto M, de la Rubia A . Determination of fluoxetine and norfluoxetine in human plasma by high-performance liquid chromatography with ultraviolet detection in psychiatric patients. J Chromatogr B Analyt Technol Biomed Life Sci. 2002; 783(1):25-31. DOI: 10.1016/s1570-0232(02)00486-5. View

14.

Lantez V, Dalle K, Charrel R, Baronti C, Canard B, Coutard B . Comparative production analysis of three phlebovirus nucleoproteins under denaturing or non-denaturing conditions for crystallographic studies. PLoS Negl Trop Dis. 2011; 5(1):e936. PMC: 3014985. DOI: 10.1371/journal.pntd.0000936. View

15.

Rodriguez P, Carrasco L . Poliovirus protein 2C contains two regions involved in RNA binding activity. J Biol Chem. 1995; 270(17):10105-12. DOI: 10.1074/jbc.270.17.10105. View

16.

Cho M, Teterina N, Egger D, Bienz K, EHRENFELD E . Membrane rearrangement and vesicle induction by recombinant poliovirus 2C and 2BC in human cells. Virology. 1994; 202(1):129-45. DOI: 10.1006/viro.1994.1329. View

17.

Teterina N, Gorbalenya A, Egger D, Bienz K, Rinaudo M, Ehrenfeld E . Testing the modularity of the N-terminal amphipathic helix conserved in picornavirus 2C proteins and hepatitis C NS5A protein. Virology. 2005; 344(2):453-67. PMC: 7111807. DOI: 10.1016/j.virol.2005.08.044. View

18.

Banerjee R, Weidman M, Echeverri A, Kundu P, Dasgupta A . Regulation of poliovirus 3C protease by the 2C polypeptide. J Virol. 2004; 78(17):9243-56. PMC: 506913. DOI: 10.1128/JVI.78.17.9243-9256.2004. View

19.

Banerjee R, Dasgupta A . Interaction of picornavirus 2C polypeptide with the viral negative-strand RNA. J Gen Virol. 2001; 82(Pt 11):2621-2627. DOI: 10.1099/0022-1317-82-11-2621. View

20.

Vance L, Moscufo N, Chow M, Heinz B . Poliovirus 2C region functions during encapsidation of viral RNA. J Virol. 1997; 71(11):8759-65. PMC: 192341. DOI: 10.1128/JVI.71.11.8759-8765.1997. View