Synthesis and biological evaluation of novel flexible nucleoside analogues that inhibit flavivirus replication in vitro.
Acyclovir
Dengue
Flavivirus
Fleximers
Methyltransferase
Nucleoside
Yellow Fever
Zika
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 11 2020
15 11 2020
Historique:
received:
23
07
2020
revised:
09
08
2020
accepted:
11
08
2020
pubmed:
1
11
2020
medline:
22
7
2021
entrez:
31
10
2020
Statut:
ppublish
Résumé
Flaviviruses, such as Dengue (DENV) and Zika (ZIKV) viruses, represent a severe health burden. There are currently no FDA-approved treatments, and vaccines against most flaviviruses are still lacking. We have developed several flexible analogues ("fleximers") of the FDA-approved nucleoside Acyclovir that exhibit activity against various RNA viruses, demonstrating their broad-spectrum potential. The current study reports activity against DENV and Yellow Fever Virus (YFV), particularly for compound 1. Studies to elucidate the mechanism of action suggest the flex-analogue triphosphates, especially 1-TP, inhibit DENV and ZIKV methyltransferases, and a secondary, albeit weak, effect on the DENV RNA-dependent RNA polymerase was observed at high concentrations. The results of these studies are reported herein.
Identifiants
pubmed: 33128910
pii: S0968-0896(20)30543-5
doi: 10.1016/j.bmc.2020.115713
pmc: PMC7457965
pii:
doi:
Substances chimiques
Antiviral Agents
0
Nucleosides
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
115713Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM066706
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
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