Ten novel sNPF analogs were designed and synthesized based on the structure of lead I-3 by molecular docking and peptidomimetic methods. Compound A-1 exhibits better binding affinity with the receptor, possesses excellent aphidicidal activity, and shows low toxicity to bees, making it a promising candidate for environmentally friendly insecticides.
ABSTRACT
Short neuropeptide F (sNPF) is a peptide unique to insects, characterized by a C-terminal phenylalanine and a conserved RLRFa motif, and plays key roles in controlling feeding behavior, growth, circadian rhythms, and water–salt homeostasis. We previously identified an sNPF analog, I-3, with aphidicidal activity. In this study, 10 sNPF analogs with aromatic or nonaromatic modifications at the N-terminus were designed based on I-3, using molecular docking and peptidomimetic strategies to investigate the role of N-terminal residues. Aphicidal activity showed that A-1 has stronger activity than I-3 and pymetrozine. Structure–activity analysis indicated that a benzene ring with electronegative and lipophilic groups at the N-terminus is key for aphicidal activity. Molecular docking and molecular dynamics simulations showed A-1 binds more stably to the receptor than I-3. Toxicity tests on honeybees (Apis mellifera) confirm that compound A-1, which exhibits strong aphidicidal activity, is safe for nontarget organisms. Additionally, Admetsar3 evaluations indicate low toxicity risks for all compounds. Therefore, A-1 represents a promising, selective, and eco-friendly insecticide for controlling pea aphids, and this study validates the feasibility of developing novel green pesticides based on sNPF.
