Zika Virus Pathogenesis and Therapeutic Prospects: Molecular Mechanisms, Neurological Implications, and Emerging Antiviral Scaffolds

Abstract

Zika virus (ZIKV), a neurotropic flavivirus transmitted primarily by Aedes mosquitoes, has emerged as a major global health threat due to its association with congenital malformations and neurological disorders such as microcephaly and Guillain–Barré syndrome. This review provides a comprehensive overview of ZIKV pathogenesis, transmission routes, and molecular mechanisms underlying host–virus interactions. Emphasis is placed on structural and functional insights into key viral enzymes NS2B–NS3 protease and NS5 RNA-dependent RNA polymerase, which serve as pivotal antiviral drug targets. Advances in structure–activity relationship (SAR) studies, small-molecule inhibitors, and natural product scaffolds, including flavonoids, alkaloids, terpenes, and thiazolides, are critically discussed as potential antiviral leads. Despite encouraging preclinical results, the absence of approved antivirals or vaccines underscores persistent challenges related to viral mutation, pharmacokinetics, and resistance. Future therapeutic success will rely on integrative approaches combining molecular modeling, artificial intelligence-guided screening, and organoid-based systems to accelerate the translation of antiviral discoveries into clinically viable interventions against ZIKV.