The Flavivirus NS3 Protein: Its Multifaceted Roles and Therapeutic Potential

Mosquito-borne flaviviruses are important human pathogenic viruses and can cause an array of symptoms ranging from asymptomatic to mild illness but can progress to severe disease conditions. Prominent members of the family Flaviviridae include Dengue virus, Zika virus, and West Nile virus, whose spread has increased globally due to the expansion of their respective mosquito vectors. Despite their importance as a public health concern, there are no FDA-approved antiviral drugs targeting these viruses in humans. One of the viral proteins essential for flavivirus replication is the NS3 protein, a highly conserved multifunctional enzyme implicated in viral polyprotein processing, viral RNA amplification, and modulation of several host cellular processes. In this review, we summarize NS3's functions in the flavivirus life cycle and its impact on clinical outcomes. We also discuss the regulation of NS3 activity through post-translational modifications and highlight ongoing research focused on developing NS3-targeted therapeutic approaches for flavivirus infections.