The future of insect repellent discovery and development

Jonathan D. Bohbot*, Daniel Strickman, Laurence J. Zwiebel

*Corresponding author for this work

Research output: Contribution to journalComment/debate

7 Scopus citations


A wide variety of arthropods act as pests that can cause catastrophic damage to food crops or take blood meals from humans and other vertebrates, and in that context, transmit pathogens and leave behind allergenic irritants in the skin. At worst, an insect bite can cause a potentially deadly infection.

At best, a bite constitutes a minor and, in some cases, a significant nuisance. Prevention of crop damage or insect bites may involve control of arthropod populations with insecticidal applications, elimination of sources, or measures taken by individuals to alter arthropod behavior so that no damage or bites occur. For vectors or nuisance insects that affect humans, such chemically-based products represent a popular means of personal protection commonly known as insect repellents.

Topical repellents are applied directly to the skin interfering with the ability of the arthropod to complete the biting process. Area repellents provide protection from arthropod bites at distance that can exceed several meters. Topical and area repellents provide protection using an arsenal of only a dozen or so active ingredients (AIs). One particular AI, N,N-diethylmeta-toluamide (DEET), has dominated the topical insect repellent market since the late 1950s. In that light, several agencies and foundations have been funding research to understand the precise mode of action of insect repellents better in order to open new research directions for the discovery and development of novel and more effective AIs. Chemically-based insect repellents can be of natural or synthetic origin. Currently, five compounds are commonly used as topical repellents including DEET (synthetic), paramenthane-3,8-diol (PMD) (occurs in botanical extracts but it can be synthesized from related compounds), hydroxyethylisobutyl piperidine carboxylate (picaridin) (synthetic), ethyl 3-acetyl(butyl)amino]propanoate (IR3535) (modified from a naturally occurring amino acid), and N,N-diethylphenyl-acetamide (DEPA) (synthetic). All exhibit several of the following characteristics: i) Large amounts of compound must be applied; ii) These compounds disrupt behavior on contact or from a short distance; iii) They affect the behavior of a wide-range of arthropods; iv) Their mode of action has not been well-established. The development of area repellents, as opposed to topical repellents, is even more challenging since AI dilution is greater in a space treatment than on a surface area. The original DEET composition patent was filed in 1946 by Samuel I. Gertler although the identification of its repellent properties was not made until 1952 at the U.S. Department of Agriculture. Starting with its release as a publicly-available product in 1957, DEET eventually replaced most of the other repellent AIs during the 1960s and 1970s. It has dominated the market due to low cost, long duration on the skin, broad spectrum of activity, and good toxicological profile. Because of these properties and its long history of use, DEET is the gold standard by which all other repellents are compared. The first evidence of the molecular mode of action of DEET suggested this compound selectively inhibits heteromeric complexes of insect odorant receptors (ORs), which are insect-specific chemosensory receptor proteins involved with the detection of airborne odorants. This model remains controversial as other studies show DEET directly activating and inhibiting ORs and adult odorant receptor neurons to evoke avoidance behaviors. In addition, more recent studies indicate that DEET activates at least two other groups of insect chemosensory receptors that act in parallel with OR-based signalling pathways. These include gustatory receptors and ionotropic receptors. Taken together it is likely that DEET interacts with several biological targets that are spread across multiple arthropod chemosensory systems; this is likely the basis for its broad spectrum of activity against a wide range of organisms. Despite its wide use and commercial success, DEET has some important weaknesses as a repellent. While its safety has been established by the U.S. Environmental Protection Agency (EPA), it suffers from negative user perception due to several factors including its odor, oilyfeel, high adsorption rate, irritating effect on occluded skin, and tendency to dissolve many kinds of plastic. In addition, DEET and other chemical repellents have a short range of action such that large quantities are required for long lasting protection. Finally, DEET is not as effective as other repellents against some mosquitoes, ticks, stable flies, and horse flies. Recent research on the mode of action of insect repellents is providing new ideas for the discovery and development of the next generation of actives that are designed to disrupt insect behavior without suffering any of the limitations of the currently available suite of repellent AIs. In this article, we will describe four basic strategies that have already yielded new discoveries that provide fertile ground for the development of novel generation of AIs that disrupt insect behavior. That said, while the basic discovery of potentially useful repellent AIs is the necessary first step; the development of these compounds into actual products will require persistence, as well as significant financial investments. The process for drug discovery and drug product development is broadly similar to the processes involved in repellent research and development, providing useful parallels to inform the risks and challenges associated with the development of novel insect repellents.

Original languageAmerican English
Pages (from-to)265-270
Number of pages6
JournalOutlooks on Pest Management
Issue number4
StatePublished - 1 Aug 2014

Bibliographical note

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  • DEET
  • Insect repellents
  • Odorant receptor
  • Product development
  • Small molecule screening


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