selective and irreversible inhibitors of aphid acetylcholinesterases steps toward human-safe insecticides蚜虫的选择性和不可逆抑制剂乙酰胆碱酯酶对人类安全杀虫剂型的步骤.pdfVIP

Selective and Irreversible Inhibitors of Aphid Acetylcholinesterases: Steps Toward Human-Safe Insecticides 1 1¤a 1 1¤b 1 2 Yuan-Ping Pang *, Sanjay K. Singh , Yang Gao , T. Leon Lassiter , Rajesh K. Mishra , Kun Yan Zhu , Stephen Brimijoin1* 1 Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America, 2 Department of Entomology, Kansas State University, Manhattan, Kansas, United States of America Abstract Aphids, among the most destructive insects to world agriculture, are mainly controlled by organophosphate insecticides that disable the catalytic serine residue of acetylcholinesterase (AChE). Because these agents also affect vertebrate AChEs, they are toxic to non-target species including humans and birds. We previously reported that a cysteine residue (Cys), found at the AChE active site in aphids and other insects but not mammals, might serve as a target for insect-selective pesticides. However, aphids have two different AChEs (termed AP and AO), and only AP-AChE carries the unique Cys. The absence of the active-site Cys in AO-AChE might raise concerns about the utility of targeting that residue. Herein we report the development of a methanethiosulfonate-containing small molecule that, at 6.0 mM, irreversibly inhibits 99% of all AChE activity extracted from the greenbug aphid (Schizaphis graminum) without any measurable inhibition of the human AChE. Reactivation studies using b-mercaptoethanol confirm that the irreversible inhibition resulted from the conjugation of the inhibitor to the unique Cys. These results suggest that AO-AChE does not contribute significantly to the overall AChE activity in aphids, thus offering new