Multi-target insect repellents for topical and spatial protection - ABSTRACT Mosquitoes use their olfactory system to find human hosts and, in the process, can transmit diseases like Malaria and Dengue to hundreds of millions of people worldwide that cause substantial mortality and morbidity. The olfactory system therefore provides an excellent target to design behavior disruption strategies. Most topical insect repellents in use (DEET, picaridin, IR3535) are effective against mosquitoes, however are rarely used by the high risk population in tropical countries due to the cost relative to incomes, the inconvenience of continuous application on skin at high concentrations and poor cosmetic properties. A more commonly used method globally is the spatial protective effect from low dose pyrethroid insecticides emitted from heated dispensers. However, the rapid spread of pyrethroid resistance in mosquitoes is cause for concern. In a recent breakthrough we have been able to develop a Machine Learning cheminformatic method to predict new repellent odorants and new pyrethroid-like molecules from in silico screening of >10 M compounds. In validating them in behavior assays, we have identified several powerful repellents from natural sources including compounds found in food and flavoring. In addition, we have identified a couple of leads for new pyrethroids, which appear to be up as effective as allethrin at a 100 x lower concentration. The goal of this proposal in 4 Aims is to identify the best-in-class insect repellent compounds and utilize them to create two types of powerful broad-spectrum blends: a topical that protects for longer at a low concentration and a spatial formulation that is more effective against knockdown resistant mosquitoes. For each blend we will also evaluate a version which has a pyrethroid component. First, we plan to rigorously validate the computationally predicted repellents in mosquito behavioral assays. Since the predictions have a variety of chemical structures, we will also use behavioral analysis of extant mutants in Aedes aegypti to identify the underlying receptor pathways responsible for aversion. Second, we plan to behaviorally evaluate volatile compounds that are known to overstimulate and disable the CO2-recpetor for their ability to mask attraction spatially. Third, we propose to validate the efficacy of the two newly discovered pyrethroids using topical and spatial assays. And fourth, we will test the dual and triple aversive pathway compounds for repellency in mosquitoes to find the most effective combination for spatial and topical repellency. Successful completion of this proposal will provide safe, affordable, and pleasant-smelling odorants that are better than existing actives in reducing contact between humans and mosquitoes.
