Exploration of 4'-fluoro fleximer nucleoside analogues as potential broad-spectrum antiviral agents

Kyle A Davis; Jason K Smith; Jessica L Smith; Meareg Amare; Meghan V Diefenbacher; Peter Halfmann; Timothy P Sheahan; Alec J Hirsch; Katherine L Seley-Radtke

doi:10.1016/j.bmc.2025.118243

Exploration of 4'-fluoro fleximer nucleoside analogues as potential broad-spectrum antiviral agents

Bioorg Med Chem. 2025 Oct 1:128:118243. doi: 10.1016/j.bmc.2025.118243. Epub 2025 May 20.

Authors

Kyle A Davis¹, Jason K Smith¹, Jessica L Smith², Meareg Amare³, Meghan V Diefenbacher⁴, Peter Halfmann³, Timothy P Sheahan⁵, Alec J Hirsch², Katherine L Seley-Radtke⁶

Affiliations

¹ Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, Baltimore, MD, USA.
² Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA.
³ Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
⁴ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, Baltimore, MD, USA. Electronic address: kseley@umbc.edu.

PMID: 40483926
PMCID: PMC12276918 (available on 2026-05-20)
DOI: 10.1016/j.bmc.2025.118243

Abstract

A series of 4'-fluoro fleximer nucleoside analogues in addition to their corresponding prodrugs were designed, synthesized, and evaluated for their antiviral potential. The impetus for this series was based on the success of other 4'-modified nucleoside antiviral drugs such as adafosbuvir and balapiravir. One analogue, KAD-008, exhibited potent, low single-digit micromolar activity against DENV-2. Another analogue, KAD-025, had broad-spectrum antiviral activity across several viral families including flaviviruses, filoviruses, and coronaviruses. All of the analogues tested showed no toxicity up to 100 µM. Additional studies are underway to elucidate the mechanism of action for these compounds and to synthesize additional 4'-modified fleximer nucleoside analogues with different 4'-modifications to compare their antiviral activities.

Keywords: Antiviral; Dengue; Fleximers; Nucleosides; Prodrugs.

MeSH terms

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

Substances

Antiviral Agents
Nucleosides

Abstract

MeSH terms

Substances

Grants and funding