Small-Molecule Agonists of Ae. aegypti Neuropeptide Y Receptor Block Mosquito Biting.

Area of Science:

• Neuroscience
• Entomology
• Pharmacology

Background:

• Female Aedes aegypti mosquitoes exhibit a strong attraction to humans for blood-feeding, crucial for egg development.
• This host-seeking behavior is temporarily suppressed after a blood meal through an unknown mechanism.

Purpose of the Study:

• To investigate the role of neuropeptide Y (NPY)-related signaling in the long-term behavioral suppression of host-seeking in Aedes aegypti.
• To identify specific receptors and develop small-molecule agonists that can modulate mosquito behavior for disease control.

Main Methods:

• Screened 49 predicted Aedes aegypti peptide receptors to identify NPY-like receptor 7 (NPYLR7) as a key target.
• Conducted a high-throughput screening of 265,211 compounds to find selective NPYLR7 agonists.
• Utilized CRISPR-Cas9 gene editing to create NPYLR7 null mutants for functional analysis.

Main Results:

• Identified NPYLR7 as the sole target of drugs that modulate mosquito host-seeking behavior.
• Isolated six highly selective NPYLR7 agonists that effectively inhibit mosquito attraction to humans.
• Demonstrated that NPYLR7 null mutants are impaired in behavioral suppression and resistant to the developed drugs.

Conclusions:

• Neuropeptide Y-related signaling, specifically through NPYLR7, plays a critical role in suppressing mosquito attraction post-blood meal.
• Developed selective NPYLR7 agonists offer a promising novel approach to control mosquito behavior and reduce infectious disease transmission.
• The study highlights the potential of targeting mosquito neurobiology for effective vector control strategies.