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Synthesis and antiviral effect of novel fluoxetine analogues as enterovirus 2C inhibitors

Manganaro, Roberto, Zonsics, Birgit, Bauer, Lisa, Lorenzo Lopez, Moira, Donselaar, Tim, Zwaagstra, Marleen, Saporito, Fabiana, Ferla, Salvatore ORCID:, Strating, Jeroen R. P. M., Coutard, Bruno, Hurdiss, Daniel L., van Kuppeveld, Frank J. M. and Brancale, Andrea ORCID: 2020. Synthesis and antiviral effect of novel fluoxetine analogues as enterovirus 2C inhibitors. Antiviral Research 178 , 104781. 10.1016/j.antiviral.2020.104781

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Enteroviruses (EV) are a group of positive-strand RNA (+RNA) viruses that include many important human pathogens (e.g. poliovirus, coxsackievirus, echovirus, numbered enteroviruses and rhinoviruses). Fluoxetine was identified in drug repurposing screens as potent inhibitor of enterovirus B and enterovirus D replication. In this paper we are reporting the synthesis and the antiviral effect of a series of fluoxetine analogues. The results obtained offer a preliminary insight into the structure-activity relationship of its chemical scaffold and confirm the importance of the chiral configuration. We identified a racemic fluoxetine analogue, 2b, which showed a similar antiviral activity compared to (S)-fluoxetine. Investigating the stereochemistry of 2b revealed that the S-enantiomer exerts potent antiviral activity and increased the antiviral spectrum compared to the racemic mixture of 2b. In line with the observed antiviral effect, the S-enantiomer displayed a dose-dependent shift in the melting temperature in thermal shift assays, indicative for direct binding to the recombinant 2C protein.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Elsevier Masson
ISSN: 0166-3542
Date of First Compliant Deposit: 8 April 2020
Date of Acceptance: 20 March 2020
Last Modified: 13 Jun 2024 17:23

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