Rational Design and Convergent Synthesis of a Cereblon-Recruiting PROTAC Targeting Dengue Virus NS3/ NS2B Protease

Dengue virus remains a major global health challenge, and its NS3/NS2B protease is essential for viral polyprotein processing, making it an attractive target for antiviral development. This work aimed to integrate structure-based design and synthetic planning to develop a cereblon-recruiting PROTAC directed toward this protease. Ten candidates were designed by connecting quercetin-derived warheads to a thalidomide-based CRBN ligand through linkers selected using structural constraints obtained from protein–protein docking and molecular dynamics simulations. These analyses identified one candidate with a favorable ternary-complex profile, which was prioritized for synthesis. The selected architecture is being assembled through a convergent five-step route centered on nucleophilic aromatic substitution, CuAAC-mediated triazole formation, and final amide coupling with the NS3-directed ligand. Overall, this workflow links computational prioritization with a modular synthetic strategy, enabling independent preparation of the molecular components and facilitating future linker diversification in structurally related PROTAC candidates.