New mode-of-action chemistries are needed to control arthropod vectors, especially where vector populations have acquired resistance to insecticides. We describe a genome-to-lead approach for discovery of novel small molecule chemistries that disrupt arthropod G protein-coupled receptor (GPCR) targets and that have potential for development as next gen insecticides. We demonstrated the utility of this approach by determining the molecular and pharmacological properties of two dopamine receptors (AaDOP1 and AaDOP2) identified from the genome sequence of the dengue vector, Aedes aegypti. We performed screens for small molecule agonists and antagonists of AaDOP2 and demonstrated that several hit chemistries are selective for the mosquito over the human dopamine receptor in vitro. These chemistries cause significant mortality of mosquito larvae 24 hours after exposure, identifying them as possible leads for insecticide development. This research demonstrates the potential of target-specific approaches that could accelerate discovery of new classes of insecticides for vector control.

Developing novel small molecule agonists and antagonists of arthropod G protein-coupled receptors as next gen insecticides for vector control

244th National Meeting (2012)

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