Disrupting Pheromone Signaling in Insects: Design, Synthesis, and Evaluation of an Inhibitor

Sex pheromones mediate mate recognition in insects through interactions with pheromone-binding proteins (PBPs). Targeting this pathway with pheromone analogs offers a species-specific approach to pest management. Here, we report the design, synthesis, and evaluation of a pheromone analog, (6E,11Z)-heptadeca-6,11-dien-1-yl acetate as an inhibitor of Antheraea polyphemus PBP1 (ApolPBP1). Molecular docking predicted potential binding orientations and interactions within the pocket. Fluorescence-based binding assays revealed a 4-fold higher dissociation constant, and 2D [¹H, ¹⁵N] HSQC NMR titrations confirmed reduced affinity, with ApolPBP1 transitioning to the bound state only at higher analog concentrations. Overall, these findings highlight the sensitivity of PBPs to subtle structural modifications in their ligands and emphasize the importance of preserving key molecular interactions for effective binding.