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Its receptor belongs to GPCR\u2010As and binds sNPF to regulate the insect nervous system. Many research groups are evaluating sNPF for plant protection and pest control. In this study, the natural sNPF from the pea aphid (<jats:styled-content style=\"fixed-case\"><jats:italic>Acyrthosiphon pisum<\/jats:italic><\/jats:styled-content>) was used as a lead compound. Five novel sNPF analogs were designed and synthesized through molecular docking and peptidomimetics, altering the N\u2010terminal amino acid to Ser, Thr, Tyr, Leu, or Gln. Aphid bioassays showed that the analog I\u20103 (YLRLRFa, LC<jats:sub>50<\/jats:sub>\u2009=\u20091.820\u2009mg\/L) was more active than the natural Acypi\u2010sNPF\u20101 and pymetrozine. The structure\u2013activity relationship analysis indicated that N\u2010terminal tyrosine incorporation, combined with increased Clog<jats:italic>P<\/jats:italic> and TPSA, enhanced aphidicidal activity. Furthermore, Toxtree's toxicity predictions suggest a low risk for all compounds, and a toxicity assay conducted on the honeybee (<jats:styled-content style=\"fixed-case\"><jats:italic>Apis mellifera<\/jats:italic><\/jats:styled-content>) for I\u20103, which exhibits high aphidicidal activity, indicates that I\u20103 does not pose a toxicity risk to non\u2010target organisms. Thus, I\u20103 can be utilized as a selective and environmentally friendly insecticide to manage pea aphids.<\/jats:p>","DOI":"10.1002\/psc.3669","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T02:33:41Z","timestamp":1737426821000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Novel Insect Short Neuropeptide sNPF Peptidomimetic Insecticide: Rational Design, Synthesis, and Aphicidal Activity Study"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8215-6763","authenticated-orcid":false,"given":"Yuanlin","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Engineering College of Chemical Engineering Sichuan University of Science &amp; Engineering  Zigong Sichuan Province 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