Small molecule NS4B inhibitors for the treatment of the family Flaviviridae infection: A medicinal chemistry perspective.

The family Flaviviridae, encompassing DENV and HCV, poses a substantial threat to global public health, with no clinically approved antiviral agents available for DENV and emerging resistance challenges complicating HCV management. NS4B has emerged as a promising antiviral target due to its indispensable roles in membrane remodeling, viral RNA replication, and innate immune evasion. This review provides a comprehensive medicinal chemistry perspective on the development of small-molecule NS4B inhibitors, systematically summarizing recent advances in structural and functional studies of DENV NS4B and HCV NS4B with particular emphasis on their critical protein-protein interactions with viral partners. We critically analyze the current landscape of small-molecule NS4B inhibitors developed over the past decade, covering diverse chemical scaffolds, including indole, imidazole, pyrazole, quinoline, thiazole, and thiophene derivatives. The SARs, mechanisms of action, and preclinical or clinical development status of these inhibitors are discussed in detail. Furthermore, we address current challenges, including drug resistance, suboptimal pharmacokinetic properties, and incomplete pan-genotypic coverage, and propose future directions for the rational design of next-generation NS4B-targeted therapeutics. This review aims to provide valuable insights for the discovery of potent antiviral agents to combat infections caused by the family Flaviviridae.