The insecticides that are currently used to control populations of disease-transmitting insect vectors act on a highly restricted set of targets. In liht of growing drug resistance, there is an urgent need to identify alternative insecticide targets. Potential candidates include G protein-coupled receptors (GPCRs) which are known to be highly "druggable" proteins. The focus of this proposal is to identify compounds that block the bursicon receptor, a GPCR that is essential for insect survival. Prior studies using both Drosophila and beetles revealed that genetic down-regulation of bursicon-mediated signaling results in defective hardening of the cuticle, inhibition of wing expansion, and compromised viability. Based on these findings, we postulate that small-molecule bursicon receptor antagonists will recapitulate these phenotypes and thus provide template structures for the development of a novel class of insecticides. Our studies will utilize Drosophila, a model system which has proven highly useful in revealing molecular mechanisms relevant to insect disease vectors. Given the extensive collections of Drosophila tools (RNAi flies, cloned cDNAs), as well as the ease of laboratory maintenance, fruit flies offer a practical starting point for the propose investigations.
In Aim 1, in collaboration with BIPDeC, we will implement a validated high-throughput screen to identify small molecule bursicon receptor antagonists. A pilot screen of 2000 compounds measuring luciferase activity as a read-out of G?s-mediated signaling linked to this GPCR revealed that our assay is highly robust, sensitive and ready for HTS.
In Aim 2, the pharmacological characteristics of "hits" will be assessed using a series of previously validated secondary/tertiary assays. These include a counter screen on an unrelated G?s coupled receptor, assessment of ligand function using an alternative index of activity (direct measurement of cAMP), as well as evaluation of potency and efficacy of putative antagonists. The most promising compounds will be tested in vivo to determine their effects on Drosophila (e.g. wing morphology and viability). The ability to follow wing expansion as a visual index of bursicon receptor blockade provides a unique advantage which will help expedite the development of antagonists that are effective in vivo.
In Aim 3, the most promising compounds will undergo structural optimization guided by both in vitro and in vivo testing. Future efforts wil utilize the chemical probes identified in this project as templates for the development of novel insecticides.

Public Health Relevance

With the alarming increase in insecticide resistance, comes an urgent need to control disease-transmitting insects using drugs that rely on new mechanisms of action. Previous genetic studies have demonstrated that the bursicon receptor is essential for insect survival. We propose to identify small molecule compounds that block this receptor and use these chemicals to assess their potential as a novel class of insecticides.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1-BST-F (50))
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Yao, Yong
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Tufts University
United States
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