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

Bioorg Med Chem. 2020 Nov 15;28(22):115713. doi: 10.1016/j.bmc.2020.115713. Epub 2020 Aug 31.

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.

Keywords: Acyclovir; Dengue; Flavivirus; Fleximers; Methyltransferase; Nucleoside; Yellow Fever; Zika.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Flavivirus / drug effects*
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry
  • Nucleosides / pharmacology*
  • Structure-Activity Relationship
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Nucleosides