Enhanced broad spectrum in vitro antiviral efficacy of 3-F-4-MeO-Bn, 3-CN, and 4-CN derivatives of lipid remdesivir nucleoside monophosphate prodrugs

Antiviral Res. 2023 Nov:219:105718. doi: 10.1016/j.antiviral.2023.105718. Epub 2023 Sep 25.

Abstract

Broad spectrum oral antivirals are urgently needed for the early treatment of many RNA viruses of clinical concern. We previously described the synthesis of 1-O-octadecyl-2-O-benzyl-glycero-3-phospho-RVn (V2043), an orally bioavailable lipid prodrug of remdesivir nucleoside (RVn, GS-441524) with broad spectrum antiviral activity against viruses with pandemic potential. Here we compared the relative activity of V2043 with new RVn lipid prodrugs containing sn-1 alkyl ether or sn-2 glycerol modifications. We found that 3-F-4-MeO-Bn, 3-CN-Bn, and 4-CN-Bn sn-2 glycerol modifications improved antiviral activity compared to V2043 when tested in vitro against clinically important RNA viruses from 5 virus families. These results support the continued development of V2043 and sn-2 glycerol modified RVn lipid prodrugs for the treatment of a broad range of RNA viruses for which there are limited therapies.

Keywords: Antiviral agents; Broad spectrum antiviral; Ebola virus; Filovirus; Flavivirus; GS-441524; GS-5734; Hemorrhagic fever viruses; Hendra virus; Henipavirus; Human coronavirus 229E; Lipid prodrugs; Nipah virus; Paramyxovirus; Pneumovirus; RNA virus; Remdesivir; Remdesivir nucleoside; Respiratory syncytial virus; Respiratory viruses; V2043; Zika virus; dengue virus.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents* / pharmacology
  • Glycerol
  • Lipids / pharmacology
  • Nucleosides / pharmacology
  • Prodrugs* / pharmacology

Substances

  • remdesivir
  • Antiviral Agents
  • Prodrugs
  • Nucleosides
  • Glycerol
  • F 4
  • Lipids