New insect repellant may be thousands of times stronger than DEET
Odorant receptors, or ORs, sit on the surface of nerve cells in the nose of mammals and in the antennae of mosquitoes. When these receptors come into contact with smelly molecules, they trigger the nerves signaling the detection of specific odors.
In the last few years, however, scientists have been surprised to learn that the olfactory system of mosquitoes and other insects is fundamentally different. In the insect system, conventional ORs do not act autonomously. Instead, they form a complex with a unique co-receptor (called Orco) that is also required to detect odorant molecules.
ORs are spread all over the antennae and each responds to a different odor. To function, however, each OR must be connected to an Orco.
“Think of an OR as a microphone that can detect a single frequency,” Zwiebel said. “On her antenna the mosquito has dozens of types of these microphones, each tuned to a specific frequency. Orco acts as the switch in each microphone that tells the brain when there is a signal. When a mosquito smells an odor, the microphone tuned to that smell will turn ‘on’ its Orco switch. The other microphones remain off,” he continued. “However, by stimulating Orco directly we can turn them all on at once. This would effectively overload the mosquito’s sense of smell and shut down her ability to find blood.”
The process of discovery
The Vanderbilt release notes that the researchers inserted mosquito odorant receptors into the human embryonic kidney cells, and tested these cells against a commercial library of 118,000 small molecules normally used in drug development.
They expected to find, and did find, a number of compounds that triggered a response in the conventional mosquito ORs they were screening, but they were surprised to find one compound that consistently triggered OR-Orco complexes, leading them to conclude that they had discovered the first molecule that directly stimulates the Orco co-receptor. They have named the compound VUAA1.
Although it is not an odorant molecule, the researchers determined that VUAA1 activates insect OR-Orco complexes in a manner similar to a typical odorant molecule. Jones also verified that mosquitoes respond to exposure to VUAA1, a crucial step in demonstrating that VUAA1 can affect a mosquito’s behavior.
“VUAA1 opens the door for the development of an entirely new class of agents, which could be used not only to disrupt disease vectors, but also the nuisance insects in your backyard or the agricultural pests in your crops,” Patrick Jones, said.
They have also established that the compound stimulates the OR-Orco complexes of flies, moths, and ants. As a result, “VUAA1 opens the door for the development of an entirely new class of agents, which could be used not only to disrupt disease vectors, but also the nuisance insects in your backyard or the agricultural pests in your crops,” Jones said.
The release also notes that many questions must be answered before VUAA1 can be considered for commercial applications. Zwiebel’s team is currently working with researchers in Vanderbilt’s Drug Discovery Program to pare away the parts of VUAA1 that do not contribute to its activity. Once that is done, they will begin testing its toxicity.
Vanderbilt University has filed for a patent on this class of compounds and is talking with potential corporate licensees interested in incorporating them into commercial products, with special focus on development of products to reduce the spread of malaria in the developing world.
— Read more in Patrick L. Jones, “Functional agonism of insect odorant receptor ion channels,” Proceedings of the National Academy of Sciences (published online before print 9 May 2011) (doi: 10.1073/pnas.1102425108)
