Recent Advances in Antiviral Medicinal Chemistry against Flaviviruses Driven by Multistrategic Approaches

Flaviviruses constitute a global health threat, mainly because of the increasing geographical spread of vectors and the suboptimal efficacy of existing prophylactic vaccines. Despite the substantial clinical burden imposed by these pathogens, a critical gap remains in the approved specific antiviral therapies. This Perspective critically evaluates recent advances in antiflaviviral drug discovery, focusing on viral nonstructural proteins (NSs), host-targeted therapeutic targets, and emerging targeted protein degradation (TPD) technologies. We highlight direct-acting antivirals (DAAs) against NS2B-NS3, NS5, and NS4B, host-targeted antivirals (HTAs) that modulate virus-dependent cellular pathways, and the transformative potential of TPD, thereby filling the gap of insufficient systematic summaries in this field. By integrating rational drug design strategies and dissecting the pharmacological profiles of agents with different scaffolds, this Perspective aims to provide a panoramic snapshot of the current landscape and a conceptual roadmap for accelerating the development of next-generation, broad-spectrum antiflaviviral drugs.