Drug Discovery of Antiviral Inhibitors Targeting Dengue Virus NS4B Protein.

Dengue virus (DENV) infection represents a rapidly growing global public health burden for which no approved antiviral therapies are currently available. Among the viral nonstructural proteins, NS4B has emerged as a particularly compelling therapeutic target despite lacking intrinsic enzymatic activity. NS4B functions as an essential membrane-associated regulator of viral replication by promoting endoplasmic reticulum remodeling, facilitating replication complex assembly, and mediating interactions with both viral and host factors. Recent phenotypic screening campaigns have identified potent pan-serotype NS4B inhibitors with several candidates advanced into clinical development, underscoring the translational promise of this target. This review outlines the DENV replication cycle with an emphasis on NS4B structure and function, summarizes recent advances in NS4B-targeted antiviral discovery, and discusses the relevant challenges and future perspectives in developing effective dengue therapeutics.