Rational design and synthesis of a safe sNPF-mimetic peptide with cross-species insecticidal activity

Short neuropeptide F (sNPF) is an insect-specific neuropeptide composed of 6-19 amino acids and features a conserved RLRFa motif, playing a pivotal role in regulating insect growth, development, feeding behavior, and energy homeostasis. Disruption of these processes can impair insect development and survival, highlighting sNPF as a promising scaffold for the development of environmentally safe insecticides in line with green chemistry principles. In the present study, ten novel sNPF analogs were rationally designed and synthesized by incorporating the conformationally rigid amino acid Aib into the previously identified lead compound I-3. Aphicidal bioassays revealed that six of these analogs exhibited higher insecticidal activity than the widely used commercial pesticide pymetrozine. Further cross-species insecticidal activity assessments demonstrated that B-5 displayed certain insecticidal or growth-inhibitory effects against six economically important pest species, including A. pisum, A. craccivora, R. padi, F. occidentalis, P. xylostella and S. frugiperda, emphasizing its potential cross-species applicability. Moreover, transcriptomic and qPCR analyses suggest that B-5 may interfere with neuropeptide signaling and suppress neural activity, thereby affecting cell development and metabolism. Honeybee toxicity assays conducted under laboratory conditions, including both contact and oral exposures, indicated that B-5 exhibits low acute toxicity to honeybees. Collectively, these findings demonstrate that B-5 is a promising lead sNPF analog with cross-species insecticidal activity and represents a potential environmentally benign, peptide-based insecticide, providing a strong foundation for the development of green and sustainable pest management strategies.