title: Insect-specific irreversible inhibitors of acetylcholinesterase in pests including the bed bug, the eastern yellowjacket, German and American cockroaches, and the confused flour beetle.
abstract: Insecticides directed against acetylcholinesterase (AChE) are facing increased resistance among target species as well as increasing concerns for human toxicity. The result has been a resurgence of disease vectors, insects destructive to agriculture, and residential pests. We previously reported a free cysteine (Cys) residue at the entrance to the AChE active site in some insects but not higher vertebrates. We also reported Cys-targeting methanethiosulfonate molecules (AMTSn), which, under conditions that spared human AChE, caused total irreversible inhibition of aphid AChE, 95% inhibition of AChE from the malaria vector mosquito (Anopheles gambia), and >80% inhibition of activity from the yellow fever mosquito (Aedes aegypti) and northern house mosquito (Culex pipiens). We now find the same compounds inhibit AChE from cockroaches (Blattella germanica and Periplaneta americana), the flour beetle (Tribolium confusum), the multi-colored Asian ladybird beetle (Harmonia axyridis), the bed bug (Cimex lectularius), and a wasp (Vespula maculifrons), with IC(50) values of approximately 1-11muM. Our results support further study of Cys-targeting inhibitors as conceptually novel insecticides that may be free of resistance in a range of insect pests and disease vectors and, compared with current compounds, should demonstrate much lower toxicity to mammals, birds, and fish.
authors.affiliation: Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Polsinelli
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Singh
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Mishra
authors.forename: Robert
authors.initials: R
authors.lastname: Suranyi
authors.forename: David W
authors.initials: DW
authors.lastname: Ragsdale
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
authors.forename: Stephen
authors.initials: S
authors.lastname: Brimijoin
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001511:Bedbugs / Q000201:enzymology; D020048:Blattellidae / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D003545:Cysteine; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D006927:Hymenoptera / Q000201:enzymology; D007313:Insecta / Q000201:enzymology*; D007306:Insecticides / Q000494:pharmacology / Q000633:toxicity; D007700:Kinetics; D008297:Male; D010526:Periplaneta / Q000201:enzymology; D013045:Species Specificity; D014231:Tribolium / Q000201:enzymology
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D000110:Acetylcholinesterase; D003545:Cysteine