Spiroindolines identify the vesicular acetylcholine transporter as a novel target for insecticide action

• Published in: PloS one Vol. 7; no. 5; p. e34712
• Main Authors: Sluder, Ann, Shah, Sheetal, Cassayre, Jérôme, Clover, Ralph, Maienfisch, Peter, Molleyres, Louis-Pierre, Hirst, Elizabeth A, Flemming, Anthony J, Shi, Min, Cutler, Penny, Stanger, Carole, Roberts, Richard S, Hughes, David J, Flury, Thomas, Robinson, Michael P, Hillesheim, Elke, Pitterna, Thomas, Cederbaum, Fredrik, Worthington, Paul A, Crossthwaite, Andrew J, Windass, John D, Currie, Richard A, Earley, Fergus G P
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2012; Public Library of Science (PLoS)
• Subjects: Acetylcholine; Acetylcholine - metabolism; Acetylcholine - pharmacokinetics; Agricultural pests; Agriculture; Agrochemicals; Amino Acid Sequence; Animal health; Animals; Antinematodal Agents - chemistry; Antinematodal Agents - metabolism; Antinematodal Agents - pharmacology; Binding sites; Biochemistry; Biological Transport - drug effects; Biology; Caenorhabditis elegans; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cells, Cultured; Chemical industry; Chemistry; Drosophila; Drosophila melanogaster; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Erosion resistance; Food supply; Genetics; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - metabolism; Heterocyclic Compounds, 4 or More Rings - pharmacology; Identification; Insect control; Insecta - growth & development; Insecta - metabolism; Insecticide resistance; Insecticides; Insecticides - chemistry; Insecticides - metabolism; Insecticides - pharmacology; Insects; Larva - drug effects; Larva - growth & development; Larva - metabolism; Medical imaging; Molecular genetics; Molecular Sequence Data; Molecular Structure; Mutagenesis; Nematicides; Nematocides; Nematodes; PC12 Cells; Pharmacology; Positron emission; Positron emission tomography; Predators; Protection and preservation; Protein Binding; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; R&D; Rats; Research & development; Sequence Homology, Amino Acid; Signal transduction; Signaling; Spiro Compounds - chemistry; Spiro Compounds - metabolism; Spiro Compounds - pharmacology; Tissues; Tomography; Toxicity; Vesamicol; Vesicular Acetylcholine Transport Proteins - genetics; Vesicular Acetylcholine Transport Proteins - metabolism; Vesicular acetylcholine transporter; North Carolina; United Kingdom > UK; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0034712

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.