Tricking the mosquito’s “nose”  pg. 4

To meet the challenge, Zwiebel and his colleagues are setting up an international research network that extends from Vanderbilt, Yale and the Netherlands to Tanzania and The Gambia. It is designed to identify odorants and the receptors that mediate attraction or repulsion to humans for An. gambiae, and then to use this information to try to reduce the transmission of malaria in areas where the disease is endemic.

The network begins in the high-tech genetic engineering and molecular biology laboratories at Vanderbilt and Yale, to identify chemical compounds that interact strongly with receptors in the female mosquito’s antennae, and which appear to be related to host selection.

The mosquito’s olfactory receptors are members of a diverse family of proteins called G protein-coupled receptors (GPCRs) that are embedded in the membranes of nearly every cell, and which are the most common conduit for signaling pathways found in nature.

Two thirds of all drugs used in humans target GPCRs. Pharmaceutical companies and academic medical centers like Vanderbilt have developed large-scale, high-throughput screens as part of their drug discovery programs to find small molecules that interact with them.

The Zwiebel group has joined forces with the drug discovery team at the Vanderbilt Institute of Chemical Biology to identify novel sets of odorants that stimulate the mosquito receptors.

These compounds will be tested in the Carlson lab at Yale for their ability to activate olfactory receptors that have been transplanted into the fruit fly, the “lab rat” of genetic research as well as in the Zwiebel lab at Vanderbilt where they will be expressed in eggs of the frog genus Xenopus, and in defined cell-culture systems.

Because Drosophila has been so extensively studied for years, it provides a platform for studying mosquito receptors that is much easier than working with Anopheles. Xenopus and cell culture systems provide addition options as well as the ability to carry out high throughput screens for active molecules.

The most interesting molecules, which the researchers have dubbed BDOCs (Behaviorally Disruptive Olfactory Compounds), will be shipped to Wageningen University, where their effects on the physiology and behavior of individual mosquitoes will be analyzed. This information will be sent back to Vanderbilt and Yale to provide additional guidance in their search for candidate compounds using medicinal chemistry approaches.

BDOCs that pass the behavioral tests will be forwarded to Tanzania, where the researchers will combine them into different blends and evaluate how they affect laboratory-reared mosquitoes in a large biosphere that simulates the natural environment. They will also explore practical methods for producing these compounds from naturally occurring sources.

Finally, the most promising blends will be field tested in cooperating villages near Ifakara and in The Gambia by members of the research team. Compounds that are effective “super-repellants” could be embedded in mosquito netting to keep mosquitoes from finding their prey, while “super-attractants” could be placed in pesticide-laden traps.

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View Related Article: How to trick the mosquito's nose: Malaria control at the molecular level