Abstract
Response to volatile environmental chemosensory cues is essential for insect survival. The odorant receptor (OR) family is an important class of receptors that detects volatile molecules. Importantly, olfaction is a key component of the multimodal approach used by mosquitoes to target and feed on humans. Current repellents have drawbacks, necessitating development of more effective agents. Insect ORs are odorant-gated ion channels, consisting of a variable odorant specificity subunit and a conserved odorant receptor co-receptor (Orco) subunit. The Orco subunit possesses an allosteric site to which modulators can bind and inhibit odorant activation of ORs. All insect ORs contain Orco, and Orco is highly conserved across diverse insect species, making this subunit an attractive target for repellent development. Here, I characterized Orco antagonists. One compound, OX1w, was shown to inhibit odorant activation of a panel of mosquito ORs activated by diverse odorants. Next, I asked whether Orco antagonist OX1w could affect insect olfactory behavior. A Drosophila melanogaster larval chemotaxis assay was utilized to address this question. Larvae were robustly attracted to highly diluted ethyl acetate. The addition of the airborne Orco antagonist OX1w to the experimental chamber abolished larval chemotaxis towards ethyl acetate. I then transitioned to a small molecule discovery project. I determined potency of structurally diverse Orco antagonists. Results were used for training machine learning algorithms to rank probable activity of a library of compounds. Testing of a representative subset of predicted active compounds revealed enrichment for Orco antagonists. Two novel Orco antagonists were able to inhibit OR-mediated olfactory behavior in the Drosophila melanogaster larval chemo-attraction assay.