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
Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics--the benzimidazoles, imidazothiazoles and macrocyclic lactones--has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.
