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Synthesis and biological evaluation of novel flexible nucleoside analogues that inhibit flavivirus replication in vitro.

Abstract：

: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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Thames JE,Waters CD 3rd,Valle C,Bassetto M,Aouadi W,Martin B,Selisko B,Falat A,Coutard B,Brancale A,Canard B,Decroly E,Seley-Radtke KL

doi

10.1016/j.bmc.2020.115713

subject

Has Abstract

pub_date

2020-08-31 00:00:00

pages

115713

issue

22

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(20)30543-5

journal_volume

28

pub_type

杂志文章

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