Novel ligands of the mosquito kinin receptor as potential adulticides

Vector-borne diseases are an increasing threat to deployed Armed Forces personnel; thus, novel pesticides and products are needed to prevent bites and disease transmission. The successful commercial insecticide/acaricide amitraz activates two tick G protein-coupled receptors (GPCRs), and this is “proof-of-principle” that GPCRs can be successful pesticide targets. We reasoned that other GPCRs in vectors, such as kinin receptors, could be similarly used for vector control by discovering novel small molecules that target these receptors. Arthropod kinins, or leucokinins, are small arthropod-specific neuropeptides that are pleiotropic in insects, acting as hormones in the hemolymph, or released centrally in the nervous system. Kinins activate GPCRs and this activation minimally requires the kinins’ last five to six carboxy-terminal amino acid residues. Such small peptides could be replaced by small synthetic molecules that could bind the receptors to disrupt kinin-regulated arthropod physiological processes. A target-specific high-throughput screen of 20,000 molecules we conducted, complemented with in silico screens, identified up to 36 antagonists of the kinin receptor and additional structural analogs were identified. In total 88 molecules were tested on females of Aedes aegypti and Culex quinquefasciatus.