Biologists Find New Class Of Insect Repellent
Scientists working in a laboratory at Vanderbilt University have potentially discovered a class of insect repellent that is 1000 times more effective than DEET and works against all types of insects.
“It wasn’t something we set out to find,” said David Rinker, a graduate student who performed the study in collaboration with graduate student Gregory Pask and post-doctoral fellow Patrick Jones. “It was an anomaly that we noticed in our tests.”
Reported in the online edition of the Proceedings of the National Academy of Sciences, the study was conducted as part of a major interdisciplinary research project to develop new ways to control the spread of malaria by disrupting a mosquito’s sense of smell. The research was supported by the Grand Challenges in Global Health Initiative funded by the Foundation for the NIH through a grant from the Bill & Melinda Gates Foundation.
“It’s too soon to determine whether this specific compound can act as the basis of a commercial product,” Laurence Zwiebel, Professor of Biological Sciences and Pharmacology at Vanderbilt, cautioned. But it is the first of its kind and, as such, can be used to develop other similar compounds that have characteristics appropriate for commercialization.”
The discovery is based on insights that the researchers have gained about the basic nature of the insect’s sense of smell in the last couple of years. Although the mosquito’s olfactory system is housed in its antennae, a decade ago biologists thought it worked in the same manner at the molecular level as it does in mammals.
A family of special proteins called odorant receptors (ORs) sits 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.
However, in the past few years, researchers have been shocked to learn that the olfactory system of mosquitoes and other insects is fundamentally different than in other creatures. In insects, conventional ORs do not act separately from one another. Instead, they form a complex, or group, with a unique co-receptor — 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,” said Zwiebel. “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. 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.”
Because the team of researchers were unable to predict which chemicals might modulate OR-Orco complexes, they decided to “throw the kitchen sink” at the problem. The researchers, using Vanderbilt’s high throughput screening facility, a technology intended for drug recovery process and not for screening of insect ORs, used genetic engineering techniques to insert mosquito odorant receptors into the human embryonic kidney cells used in the screening process. They then tested these cells against a commercial library of 118,000 small molecules normally used in drug development.
The researchers found a number of compounds that triggered a response in the conventional mosquito ORs they were screening, but they were astounded to find one compound that consistently triggered OR-Orco complexes, leading them to conclude that they had found the first molecule that directly stimulates the Orco co-receptor. They named the compound VUAA1.
Although VUAA1 is not an odorant molecule, the team determined that it activates insect OR-Orco complexes in a manner similar to a typical odorant molecule. The team also verified that mosquitoes respond to exposure to VUAA1, a critical step in demonstrating that VUAA1 can affect a mosquito’s behavior.
“If a compound like VUAA1 can activate every mosquito OR at once, then it could overwhelm the insect’s sense of smell, creating a repellant effect akin to stepping onto an elevator with someone wearing too much perfume, except this would be far worse for the mosquito,” said Jones.
In preliminary tests with mosquitoes, the team found that VUAA1 is thousands of times more effective than DEET. They also confirmed 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.
More study is needed before VUAA1 can be considered for commercial use. Zwiebel’s team is now working with researchers in Vanderbilt’s Drug Discovery Program to slice away the parts of VUAA1 that do not contribute to its activity. Once that is done, they will begin testing toxicity.
Vanderbilt has filed for patent on this class of compounds and is seeking potential corporate licensees interesting in commercializing the compounds. They are especially focusing on development of products to reduce the spread of malaria in the developing world.
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