title: Spiroindolines identify the vesicular acetylcholine transporter as a novel target for insecticide action.
abstract: The efficacy of all major insecticide classes continues to be eroded by the development of resistance mediated, in part, by selection of alleles encoding insecticide insensitive target proteins. The discovery of new insecticide classes acting at novel protein binding sites is therefore important for the continued protection of the food supply from insect predators, and of human and animal health from insect borne disease. Here we describe a novel class of insecticides (Spiroindolines) encompassing molecules that combine excellent activity against major agricultural pest species with low mammalian toxicity. We confidently assign the vesicular acetylcholine transporter as the molecular target of Spiroindolines through the combination of molecular genetics in model organisms with a pharmacological approach in insect tissues. The vesicular acetylcholine transporter can now be added to the list of validated insecticide targets in the acetylcholine signalling pathway and we anticipate that this will lead to the discovery of novel molecules useful in sustaining agriculture. In addition to their potential as insecticides and nematocides, Spiroindolines represent the only other class of chemical ligands for the vesicular acetylcholine transporter since those based on the discovery of vesamicol over 40 years ago, and as such, have potential to provide more selective tools for PET imaging in the diagnosis of neurodegenerative disease. They also provide novel biochemical tools for studies of the function of this protein family.
authors.affiliation: Cambria Biosciences, Woburn, Massachusetts, United States of America.
authors.forename: Ann
authors.initials: A
authors.lastname: Sluder
authors.forename: Sheetal
authors.initials: S
authors.lastname: Shah
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cassayre
authors.forename: Ralph
authors.initials: R
authors.lastname: Clover
authors.forename: Peter
authors.initials: P
authors.lastname: Maienfisch
authors.forename: Louis-Pierre
authors.initials: LP
authors.lastname: Molleyres
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hirst
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Flemming
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.forename: Penny
authors.initials: P
authors.lastname: Cutler
authors.forename: Carole
authors.initials: C
authors.lastname: Stanger
authors.forename: Richard S
authors.initials: RS
authors.lastname: Roberts
authors.forename: David J
authors.initials: DJ
authors.lastname: Hughes
authors.forename: Thomas
authors.initials: T
authors.lastname: Flury
authors.forename: Michael P
authors.initials: MP
authors.lastname: Robinson
authors.forename: Elke
authors.initials: E
authors.lastname: Hillesheim
authors.forename: Thomas
authors.initials: T
authors.lastname: Pitterna
authors.forename: Fredrik
authors.initials: F
authors.lastname: Cederbaum
authors.forename: Paul A
authors.initials: PA
authors.lastname: Worthington
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Crossthwaite
authors.forename: John D
authors.initials: JD
authors.lastname: Windass
authors.forename: Richard A
authors.initials: RA
authors.lastname: Currie
authors.forename: Fergus G P
authors.initials: FG
authors.lastname: Earley
mesh_terms: D000109:Acetylcholine / Q000378:metabolism* / Q000493:pharmacokinetics; D000595:Amino Acid Sequence; D000818:Animals; D000969:Antinematodal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007313:Insecta / Q000254:growth & development / Q000378:metabolism*; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007814:Larva / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016716:PC12 Cells; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000969:Antinematodal Agents; D029742:Caenorhabditis elegans Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D007306:Insecticides; D020033:Protein Isoforms; D013141:Spiro Compounds; C082365:Unc-17 protein, C elegans; D050494:Vesicular Acetylcholine Transport Proteins; D000109:Acetylcholine