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 metadata

Cited literature [69 references]  Display  Hide  Download
Contributor : bruno coutard Connect in order to contact the contributor
Submitted on : Tuesday, December 17, 2019 - 10:05:30 PM
Last modification on : Wednesday, November 3, 2021 - 5:49:36 AM
Long-term archiving on: : Wednesday, March 18, 2020 - 6:40:57 PM


Publication funded by an institution




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⟩



Record views


Files downloads