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bioRxiv · 10.1101/2024.02.28.582529

Next Generation Neuropeptide Y Receptor Small Molecule Agonists Inhibit Mosquito Biting Behavior

Zeledon, E. V.·Baxt, L. A.·Khan, T. A.·Michino, M.·Miller, M.·Huggins, D. J.·Jiang, C. S.·Vosshall, L. B.·Duvall, L. B.
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Abstract

Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like Receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small molecule NPYLR7 agonists that suppress host-seeking and blood feeding when fed to mosquitoes at high micromolar doses. Using structure activity relationship analysis and structure-guided design we synthesized 128 compounds with similarity to known NPYLR7 agonists. Although in vitro potency (EC50) was not strictly predictive of in vivo effect, we identified 3 compounds that suppressed blood feeding from a live host when fed to mosquitoes at a 1 M dose, a 100-fold improvement over the original reference compound. Exogenous activation of NPYLR7 represents an innovative vector control strategy to block mosquito biting behavior and prevent mosquito/human host interactions that lead to pathogen transmission.

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Zeledon, E. V., Baxt, L. A., Khan, T. A., Michino, M., Miller, M., Huggins, D. J., Jiang, C. S., Vosshall, L. B., Duvall, L. B.. 2024-03-02. Next Generation Neuropeptide Y Receptor Small Molecule Agonists Inhibit Mosquito Biting Behavior. https://doi.org/10.1101/2024.02.28.582529

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