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

• Published in: Parasites & vectors 2024-06, Vol.17 (1), p.276-12, Article 276
• 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: Article
• Language: English
• Subjects: Aedes - drug effects; Aedes aegypti; Analysis; Animals; Bites and stings; Control; Disease transmission; Egg industry; Feeding Behavior - drug effects; Female; Host-seeking; Humans; Identification and classification; Mosquito; Mosquito Vectors - drug effects; Mosquitoes; Neuropeptide Y; Observations; Prevention; Receptors, Neuropeptide Y - agonists; Receptors, Neuropeptide Y - metabolism; Small-molecule agonist; Structure-Activity Relationship; Structure-guided design
• ISSN: 1756-3305; 1756-3305
• DOI: 10.1186/s13071-024-06347-w

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. Using structure-activity relationship analysis and structure-guided design we synthesized 128 compounds with similarity to known NPYLR7 agonists. Although in vitro potency (EC ) 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. 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.