Bauer, Lisa, Manganaro, Roberto, Zonsics, Birgit, Strating, Jeroen R. P. M., El Kazzi, Priscila, Lorenzo Lopez, Moira, Ulferts, Rachel, van Hoey, Clara, Maté, Maria J., Langer, Thierry, Coutard, Bruno, Brancale, Andrea  ORCID: https://orcid.org/0000-0002-9728-3419 and van Kuppeveld, Frank J. M.
2019.
Fluoxetine inhibits enterovirus replication by targeting the viral 2C protein in a stereospecific manner.
ACS Infectious Diseases
5
(9)
, pp. 1609-1623.
10.1021/acsinfecdis.9b00179
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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.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Pharmacy |
| Publisher: | American Chemical Society |
| ISSN: | 2373-8227 |
| Date of First Compliant Deposit: | 10 September 2019 |
| Date of Acceptance: | 15 July 2019 |
| Last Modified: | 05 Jan 2024 05:47 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/125391 |
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