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

• Published in: bioRxiv
• Main Authors: 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
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 05.03.2024
• Subjects: Aedes aegypti; Agonists; Biting behavior; Culicidae; Egg production; Mosquitoes; Neuropeptide Y; Neuropeptides; Pathogens
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.02.28.582529

Female 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 potency (EC ) was not strictly predictive of effect, we identified 3 compounds that suppressed blood feeding from a live host when fed to mosquitoes at a 1 μM 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.