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.
Highlights
Increasing demand for food, fuel and fibre crops from limited agricultural land area will drive more intensive agricultural practices that are more vulnerable to losses from pests and disease
We report the discovery of an insecticide class that acts at the vesicular acetylcholine transporter, a novel target for insect control
Intrigued by a possible extension of the privileged nature of this structural scaffold to crop protection research, we embarked on an optimization program around this initial lead which resulted in the identification of highly potent and selective insecticides such as SYN351 and SYN876 [14]
Summary
Increasing demand for food, fuel and fibre crops from limited agricultural land area will drive more intensive agricultural practices that are more vulnerable to losses from pests and disease. Reliable insect control requires the development of novel insecticides that overcome resistance against existing classes in pest populations, and this is an issue for all major agrochemical classes, and has become a critical issue for human and animal health [4,5,6]. We report the discovery of an insecticide class that acts at the vesicular acetylcholine transporter, a novel target for insect control. Identification of this protein as the target delivering the insecticidal effect was driven by a forward genetics approach in model organisms and harnessed the gene function knowledge base in the free living nematode Caenorhabditis elegans
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