Development of Prodrugs for Antiviral Therapies

Nucleoside derivatives have been utilized as antiviral agents for decades, targeting various viruses. These compounds enter cells via transporters or passive diffusion, where they are phosphorylated by nucleoside kinases into active metabolites. However, due to structural differences from natural nucleosides, these derivatives face limitations, such as inefficient phosphorylation, poor membrane permeability, and low oral bioavailability, often leading to resistance through the downregulation of transport proteins or dephosphorylation by phosphatases. To overcome these limitations, phosphoramidate prodrugs have been developed, which enhance stability and transport efficiency by incorporating lipophilic groups into the monophosphate structure. This research aims to synthesize prodrugs of nucleosides containing lipid-conjugated prodrugs and evaluate their antiviral efficacy.