Rational Design, Synthesis, and Aphicidal Activity of Novel Insect Short Neuropeptide Analogs as Potential Aphid Control Agents

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.