Synthesis and antiviral effect of novel fluoxetine analogues as enterovirus 2C inhibitors.
Animals
Antiviral Agents
/ chemical synthesis
Carrier Proteins
/ antagonists & inhibitors
Cell Line
Cytopathogenic Effect, Viral
/ drug effects
Enterovirus B, Human
/ drug effects
Enterovirus D, Human
/ drug effects
Fluoxetine
/ analogs & derivatives
HeLa Cells
Humans
Stereoisomerism
Structure-Activity Relationship
Viral Nonstructural Proteins
/ antagonists & inhibitors
2C Inhibitors
Enterovirus
Fluoxetine
Thermal shift assay
Journal
Antiviral research
ISSN: 1872-9096
Titre abrégé: Antiviral Res
Pays: Netherlands
ID NLM: 8109699
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
29
10
2019
revised:
18
03
2020
accepted:
20
03
2020
pubmed:
3
4
2020
medline:
27
3
2021
entrez:
3
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32234539
pii: S0166-3542(19)30618-7
doi: 10.1016/j.antiviral.2020.104781
pii:
doi:
Substances chimiques
Antiviral Agents
0
Carrier Proteins
0
Viral Nonstructural Proteins
0
Fluoxetine
01K63SUP8D
2C protein, viral
EC 3.6.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
104781Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.