Lipid-conjugated nucleoside prodrugs for antiviral therapy

Nucleoside analogs have served as the cornerstone of antiviral therapy by acting as antimetabolites that disrupt viral DNA or RNA synthesis, thereby effectively inhibiting viral replication. Despite their clinical success, many nucleoside-based antivirals suffer from intrinsic limitations such as poor lipophilicity, low membrane permeability, and rapid metabolic degradation, all of which compromise oral bioavailability and therapeutic efficacy. To address these challenges, lipid conjugation has emerged as a promising prodrug strategy that enhances pharmacokinetic properties, improves cellular uptake, and enables targeted delivery. This approach not only improves drug absorption and stability but also offers the potential to reduce toxicity and broaden antiviral indications. In this review, we summarize the design strategies, pharmacological benefits, and antiviral performance of lipid-conjugated nucleoside prodrugs, with a focus on FDA-approved agents. By analyzing recent developments in this field, we aim to provide insights that may inform the rational design of next-generation lipid-based antiviral therapeutics.