Skip to Main content Skip to Navigation
Journal articles

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

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.
Complete list of metadatas

Cited literature [69 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-02416968
Contributor : Bruno Coutard <>
Submitted on : Tuesday, December 17, 2019 - 10:05:30 PM
Last modification on : Tuesday, May 26, 2020 - 3:18:49 AM
Long-term archiving on: : Wednesday, March 18, 2020 - 6:40:57 PM

File

acsinfecdis.9b00179.pdf
Publication funded by an institution

Identifiers

Collections

Citation

Lisa Bauer, Roberto Manganaro, Birgit Zonsics, Jeroen Strating, Priscila El Kazzi, et al.. Fluoxetine Inhibits Enterovirus Replication by Targeting the Viral 2C Protein in a Stereospecific Manner. ACS Infectious Diseases, American Chemical Society, 2019, 5 (9), pp.1609-1623. ⟨10.1021/acsinfecdis.9b00179⟩. ⟨inserm-02416968⟩

Share

Metrics

Record views

128

Files downloads

198