Nucleoside and Nucleotide analogs, acting as antimetabolites or inhibitors that interfere with DNA or RNA synthesis, have been extensively utilized in the treatment of various viral infections [1,2]. Nucleoside analogs require transport by such as the human equilibrative nucleoside transporter 1 (hENT1) to enter cells. [3] Upon cellular uptake, a nucleoside analog undergoes its first phosphorylation by cellular kinases. This reaction converts the nucleoside into a nucleoside monophosphate, its initial nucleotide form. The formation of this first nucleotide is often the rate-limiting step. To overcome this challenge, nucleotide analog prodrugs employ a ‘kinase bypass’ strategy, notably the ProTide technology, thereby avoiding this inefficient enzymatic step. [4] Following two subsequent phosphorylation, this nucleotide is converted into its active triphosphate form. This final active nucleotide can then be incorporated into a growing nucleic acid chain, thereby inhibiting its elongation. In addition to serving as chain terminators upon incorporation into nucleic acids, certain nucleoside and nucleotide analogs can also act as direct inhibitors of viral polymerases and other enzymes involved in nucleic acid metabolism, thereby further impairing viral replication. This process effectively inhibits the replication of both DNA and RNA viruses. [5,6] Despite the therapeutic efficacy of nucleoside and nucleotide analogs, inherent limitations related to drug delivery and drug resistance exist. These compounds are generally hydrophilic, resulting in low bioavailability and challenges in crossing the blood-brain barrier. [7] To overcome these limitations, the strategy of conjugating lipids to nucleosides or nucleotides has emerged as a promising approach [8,9]. Lipid-conjugated prodrugs have attracted considerable interest due to their potential to enhance absorption and membrane permeability, improve chemical and metabolic stability, increase pharmacological activity, and minimize side effects [7,10]. Some studies suggest that lipid conjugation can facilitate targeted delivery to specific tissues or cells and reduce overall toxicity [11]. Thus, lipid conjugation offers a versatile strategy to enhance the efficacy and safety of existing nucleoside and nucleotide analogs.

Given these advantages, lipid-based modifications represent a promising avenue for optimizing nucleoside antivirals. This review aims to provide a comprehensive analysis of FDA-approved nucleoside or nucleotide-based antiviral agents and evaluate their development as lipid prodrugs. By identifying common structural strategies, pharmacokinetic improvements, and clinical benefits, we hope to offer valuable insights to guide the rational design of next-generation lipid-based antiviral therapeutics.