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

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.