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.
Subject(s)
Acetylcholine/metabolism , Heterocyclic Compounds, 4 or More Rings/metabolism , Insecta/metabolism , Insecticides/metabolism , Spiro Compounds/metabolism , Vesicular Acetylcholine Transport Proteins/metabolism , Acetylcholine/pharmacokinetics , Amino Acid Sequence , Animals , Antinematodal Agents/chemistry , Antinematodal Agents/metabolism , Antinematodal Agents/pharmacology , Biological Transport/drug effects , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Cells, Cultured , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Insecta/growth & development , Insecticides/chemistry , Insecticides/pharmacology , Larva/drug effects , Larva/growth & development , Larva/metabolism , Molecular Sequence Data , Molecular Structure , PC12 Cells , Protein Binding , Protein Isoforms/genetics , Protein Isoforms/metabolism , Rats , Sequence Homology, Amino Acid , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Vesicular Acetylcholine Transport Proteins/geneticsABSTRACT
In vivo high throughput screening (HTS) has been adopted by most of the larger crop protection companies as an important tool for the discovery of new agrochemicals. There has been a paradigm shift in capabilities from screening a few thousand compounds a year to several hundred thousand and the quantity of screening sample required has fallen dramatically. The unifying goal now bringing together screens and inputs is the need to maximise the flow of useful information from HTS and thereby minimise the time taken to discover robust leads and new products. This review examines the positive changes that have occurred towards targeted design and selection of chemical inputs for agrochemical discovery over the last ten years and corresponding developments in HTS assays, data analysis and the logistics of compound storage and dispensing.
