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Research News at Vanderbilt

New insect repellant may be thousands of times stronger than DEET

by | Posted on Monday, May. 9, 2011 — 2:00 PM

Colored scanning electron micrograph image of an Anopheles mosquito that spreads malaria. (Copyright © 2011 Photo Researchers, Inc. All Rights Reserved.)

Colored scanning electron micrograph image of an Anopheles mosquito that spreads malaria. (Copyright © 2011 Photo Researchers, Inc. All Rights Reserved.)

Imagine an insect repellant that not only is thousands of times more effective than DEET – the active ingredient in most commercial mosquito repellants – but also works against all types of insects, including flies, moths and ants.

That possibility has been created by the discovery of a new class of insect repellant made in the laboratory of Vanderbilt Professor of Biological Sciences and Pharmacology Laurence Zwiebel and reported this week in the online Early Edition of the Proceedings of the National Academy of Sciences.

In preliminary tests with mosquitoes, the researchers found the new class of repellant,  called Vanderbilt University Allosteric Agonist or VUAA1, to be thousands of times more effective than DEET. The compound works by affecting insects’ sense of smell through a newly discovered molecular channel.

“If a compound like VUAA1 can activate every mosquito odorant receptor 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 Patrick Jones, a post-doctoral fellow who conducted the study with graduate students David Rinker and Gregory Pask.

The researchers have just begun behavioral studies with the compound.

“It’s too soon to determine whether this specific compound can act as the basis of a commercial product,” Zwiebel 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 was made during tests that are 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 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.

Graduate student David Rinker. (Susan Urmy, Vanderbilt University)

Graduate student David Rinker. (Susan Urmy / Vanderbilt)

“It wasn’t something we set out to find,” Rinker said. “It was an anomaly that we noticed in our tests.”

A different sense of smell

The discovery of this new class of repellant is based on insights that scientists have gained about the basic nature of the insect’s sense of smell in the last few years. Although the mosquito’s olfactory system is housed in its antennae, 10 years ago biologists thought that it worked in the same way at the molecular level as it does in mammals. 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.

Professor Laurence Zwiebel talking with a student in the lab. (Neil Brake, Vanderbilt University)

Professor Laurence Zwiebel talking with a student in the lab. (Neil Brake / Vanderbilt)

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

Because the researchers couldn’t predict what chemicals might modulate OR-Orco complexes, they decided to “throw the kitchen sink” at the problem. Through their affiliation with Vanderbilt’s Institute of Chemical Biology, they gained access to Vanderbilt’s high throughput screening facility, a technology intended for the drug discovery process.

Post-doctoral fellow Patrick Jones. (Susan Urmy, Vanderbilt University)

Post-doctoral fellow Patrick Jones. (Susan Urmy / Vanderbilt)

Jones used genetic engineering techniques to insert mosquito odorant receptors into the human embryonic kidney cells used in the screening process. Rinker 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.

Graduate student Gregory Pask. (Susan Urmy, Vanderbilt University)

Graduate student Gregory Pask. (Susan Urmy / Vanderbilt)

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.

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.

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 don’t 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.




Previous stories on mosquito olfaction research:


Contact:
David Salisbury, (615) 322-NEWS
david.salisbury@vanderbilt.edu


  • http://twitter.com/Aahron0 Peter Peter

    Is this a protein? More relevant… it has enough vapor pressure to be useful for repelency/attraction?

    • http://www.vanderbilt.edu Melanie Moran

      Peter – Here is the response from Patrick Jones, one of the researchers:

      “VUAA1 is not a protein, it is a small molecule ( a chemical compound).

      VUAA1 is a first generation compound that has demonstrated limited volatility. We are actively working towards developing new VUAA1 analogs with increased volatility to enhance their capacity as repellents.”

  • Guest

    This is an amazing discovery, but also a little disconcerting. We’re talking about a compound that can disrupt multiple classes of insects’ ability to find food. Has anyone considered the ecological impact that might have? Insects die of starvation, causing birds, rodents, etc to die of starvation, and so on. A worst case scenario of this could be horrible. I truly hope people will put a LOT of forethought and testing into this before anything is commercialized.

    • http://www.vanderbilt.edu Melanie Moran

      From one of the researchers, Patrick Thomas: “The ability to repel many different types of insects is indeed a double-edged sword. We agree that if such a compound were to be used irresponsibly it could have ecological consequences, the same as if an insecticide were to be used irresponsibly (e.g. DDT). We anticipate that with the responsible application of a compound like VUAA1, any off-target effects could be mitigated. By limiting the timing, doseage, and spatial application of such a repellent, one could reduce the effects on beneficial insects. In this context, the beauty of a repellent is that it would keep pests off of crops (or people) but force them to other food resources all the while keeping them alive and in the food chain. The EPA has strict protocols set in place to assess the potential human health and environmental effects of such agents, and these will assuredly be followed. “

  • http://twitter.com/Aahron0 Peter Peter

    Many thanks Melanie. Then what means “it is not an odorant molecule”? I assume that either is NOT a small molecule as most of semiochemicals and/or has not appreciable vapor pressure. In that case… The activity would work on direct contact.

    • http://www.vanderbilt.edu Melanie Moran

      Might be easiest to email the researcher who answered this directly. His address is: patrick.l.jones@Vanderbilt.Edu

  • http://twitter.com/Aahron0 Peter Peter

    In a paper of mine of 2001 I cited as remarkable works those of Axel, Buck, Vosshall. And Zweibel. The first one received the Nobel Price short after publication (unexpected for this kind of research). Now Zweibel is on the list of “brilliant odorists” . Anyone wants to now who will be next one? I may know it!

  • Guest

    It doesn’t appear that DEET is mentioned anywhere in the article in PNAS, where are the results for this claim???  Do mosquitos avoid people with this chemical on their arm?

    • http://www.vanderbilt.edu Melanie Moran

      The DEET comparison is based on preliminary behavioral studies that were not included in the PNAS paper but will be published in the near future. Currently, there is no information available about the compound’s toxicity, so more research must be done before it is tested on humans.

  • John Darwin Namata

    I really wonder what is chemical structure of the OR and orco that makes it reactive to volatile compounds. Is there any lead on the structure of both?

    • http://news.vanderbilt.edu Vanderbilt News Service

      Vanderbilt Professor of Biological Sciences and Pharmacology Laurence Zwiebel responds, “As of yet there is no really precise or even informative structural information as to Orcos in general and accordingly we can not say much about how these proteins might interact with VUAA1.”

  • VaL

    Please fast track this, I can only go outside a few months of the year, mosquitoes love me for some reason, even the over wintering ones mob me. Wish i could volunteer as a guinea pig test subject.

  • http://BoxOnline.com/ Ted Box

    Can vuaa1 be mass produced? Can its effect be limited to mosquitos? Does vuaa1 have any effect on animals that feed on mosquitos?