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Fluoxetine Inhibits Enterovirus Replication by Targeting the Viral 2C Protein in a Stereospecific Manner

Authors
  • Bauer, Lisa1
  • Manganaro, Roberto2
  • Zonsics, Birgit2
  • Strating, Jeroen R. P. M.1
  • El Kazzi, Priscila3
  • Lorenzo Lopez, Moira2
  • Ulferts, Rachel1
  • van Hoey, Clara4
  • Maté, Maria J.3
  • Langer, Thierry4
  • Coutard, Bruno3, 5
  • Brancale, Andrea2
  • van Kuppeveld, Frank J. M.1
  • 1 Utrecht University, The Netherlands
  • 2 Cardiff University, United Kingdom , (United Kingdom)
  • 3 Aix-Marseille Université, France , (France)
  • 4 University of Vienna, Austria , (Austria)
  • 5 Unité des Virus Emergents, France , (France)
Type
Published Article
Journal
ACS Infectious Diseases
Publisher
American Chemical Society
Publication Date
Jul 15, 2019
Volume
5
Issue
9
Pages
1609–1623
Identifiers
DOI: 10.1021/acsinfecdis.9b00179
PMID: 31305993
PMCID: PMC6747591
Source
PubMed Central
Keywords
License
Unknown

Abstract

Enteroviruses (family Picornaviridae ) comprise a large group of human pathogens against which no licensed antiviral therapy exists. Drug-repurposing screens uncovered the FDA-approved drug fluoxetine as a replication inhibitor of enterovirus B and D species. Fluoxetine likely targets the nonstructural viral protein 2C, but detailed mode-of-action studies are missing because structural information on 2C of fluoxetine-sensitive enteroviruses is lacking. We here show that broad-spectrum anti-enteroviral activity of fluoxetine is stereospecific concomitant with binding to recombinant 2C. ( S )-Fluoxetine inhibits with a 5-fold lower 50% effective concentration (EC50) than racemic fluoxetine. Using a homology model of 2C of the fluoxetine-sensitive enterovirus coxsackievirus B3 (CVB3) based upon a recently elucidated structure of a fluoxetine-insensitive enterovirus, we predicted stable binding of ( S )-fluoxetine. Structure-guided mutations disrupted binding and rendered coxsackievirus B3 (CVB3) resistant to fluoxetine. The study provides new insights into the anti-enteroviral mode-of-action of fluoxetine. Importantly, using only ( S )-fluoxetine would allow for lower dosing in patients, thereby likely reducing side effects.

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