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| |  Efforts to control the spread of malaria face serious challenges, including the parasite’s increased resistance to both medications and insecticides and environmental concerns about the use of traditional insecticides.
Mosquitoes that spread malaria parasites use their sense of smell to find human hosts, most often by cueing in on the scent of human sweat and the carbon dioxide present in breath. Drs. Axel and Vosshall and their colleagues are seeking to develop a new generation of insect repellents that work by disrupting the olfactory system of the Anopheles mosquito, the primary vector in Africa.
Recent advances in molecular genetics have provided a wealth of information about the specific odorant receptor proteins that underlie the exquisitely sensitive olfactory behavior of mosquitoes. The project team is using this knowledge as a guide to develop small molecules that will function as antagonists of insect chemosensory receptors in cell-based assays, and hopes to optimize these eventually to control Anopheles olfactory behavior in the field.
After assay development of a cell line expressing GPRGR2+GPRGR7, investigators have begun a small molecule pilot screening. Investigators plan to re-screen primary hits. Their hope is to find lead compounds that can be optimized and developed into second-generation insect repellants to replace the most common ingredients in today's commercial formulations, DEET and Picaridin. |
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| | | Identify Anopheles odorant and CO2 receptor genes | | | | | Screen small compound libraries to identify odorant and CO2 receptor agonists and antagonists | | | | | Validate lead compounds in functional assays, using both Drosophila (fruit flies) and Anopheles, measuring odor-invoked locomotor activity | | | | | Optimize repellent compounds based on structure-activity relationships and re-assess in the cell-based and behavioral assays. | | | | | Develop cell-based calcium assays for insect odorant and CO2 receptors. | | |
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| | | Investigators have defined the molecular basis of CO2 detection in Drosophila and extended this to identify candidate CO2 receptors in Anopheles mosquitoes. They also established cell-based calcium assays that allow them to reconstitute insect smell in a tissue culture cell, and have moved these cell-based assays to a miniaturized 384-well plate format in preparation for screening through a library of 100,000 small compounds for potential inhibitors of the insect odorant receptors. | | | | | The project team proceeded with assay development of a cell line expressing GPRGR2+GPRGR7, an odorant receptor complex from An. gambiae. After optimization , investigators have begun a small molecule pilot screen. | | | | In parallel research efforts, investigators have produced evidence that insect odorant receptors are not G protein-coupled receptors but odor-gated non-selective cation channels. They have investigated the mechanism of action of existing insect repellents DEET and Picaridin, and have shown that the compounds selectively inhibit a subset of mosquito olfactory sensory neurons tuned to attractive human volatiles. | | |
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