2024

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

Zeledon, Emely V.; Baxt, Leigh A.; Khan, Tanweer A.; Michino, Mayako; Miller, Michael; Huggins, David J.; Jiang, Caroline S.; Vosshall, Leslie B.; Duvall, Laura B.

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.


Graphical Abstract