Acetyl-CoA Carboxylase\nProteolysis-Targeting Chimeras:\nConceptual Design and Application as Insecticides

Novel approaches for pest control are essential to ensure\na sufficient\nfood supply for the growing global population. The development of\nnew insecticides must meet rigorous regulatory requirements for safety\nand address the resistance issues of existing insecticides. Proteolysis-targeting\nchimeras (PROTACs), originally developed for human diseases, show\npromise in agriculture. They offer innovative insecticides tailored\nto overcome resistance, opening avenues for agricultural applications.\nIn this study, we developed small-molecule degraders by incorporating\npomalidomide as an E3 ligand. These degraders were linked to a ligand\n(spirotetratmat enol) targeting the ACC protein through a flexible\nchain, aiming to achieve the efficient control of insects. Compounds <b>9a</b>–<b>9d</b> were designed, synthesized, and\nevaluated for biological activities and mechanisms. Among them, <b>9b</b> exhibited superior potency against Aphis\ncraccivora (LC<sub>50</sub> = 107.8 μg mL<sup>–1</sup>) compared to others and effectively degraded ACC\nproteins through the ubiquitin-proteasome system. These findings highlight\nthe potential of utilizing PROTAC-based approaches in the development\nof insecticides for efficient pest control.