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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.
Cited literature [69 references]
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
Document(s) archivé(s) le : Wednesday, March 18, 2020 - 6:40:57 PM
Contributor : Bruno Coutard <>
Submitted on : Tuesday, December 17, 2019 - 10:05:30 PM
Last modification on : Tuesday, May 26, 2020 - 3:18:49 AM
Document(s) archivé(s) le : Wednesday, March 18, 2020 - 6:40:57 PM
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acsinfecdis.9b00179.pdf
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