Assessing the Design of Pyrimidine-Based Nucleoside Analogs Targeting Dengue and Zika RNA-Dependent RNA Polymerase: What are the Rules?

Arboviral infections, particularly Dengue and Zika, continue to rise at an alarming rate, with both viruses declared global health emergencies in 2024 and 2016, respectively. The NS5 RNA-dependent RNA polymerase (RdRp) of dengue virus (DENV) and Zika virus (ZIKV) is highly conserved, making nucleoside-based RdRp inhibitors a promising strategy for antiviral development. While nucleoside analogs have shown strong clinical potential, challenges such as cell permeability, the efficiency of triphosphate conversion, degradation, and mitochondrial toxicity remain. Advances in sugar ring modifications and prodrug approaches have addressed many of these liabilities, yet no FDA-approved treatments currently exist for DENV or ZIKV. This perspective summarizes key efforts taken to develop pyrimidine-based nucleosides as anti-DENV and anti-ZIKV therapeutics, and highlight challenges in developing nucleotide prodrugs for nonliver-targeted viral infections. This perspective will help the antiviral field design the next-generation nucleoside-based therapeutics with potent antiflavivirus activity and reduced toxicity.