Next-generation neuropeptide Y receptor small-molecule agonists inhibit mosquito-biting behavior.

Background: 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 inhibit host-seeking and blood-feeding when fed to mosquitoes at high micromolar doses. Methods: Using structure–activity relationship analysis and structure-guided design we synthesized 128 compounds with similarity to known NPYLR7 agonists. Results: Although in vitro potency (EC50) was not strictly predictive of in vivo effect, we identified three compounds that reduced blood-feeding from a live host when fed to mosquitoes at a dose of 1 μM—a 100-fold improvement over the original reference compound. Conclusions: 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. [ABSTRACT FROM AUTHOR]