Three small molecules were identified in high throughput screens that 1) block renal inward rectifier potassium (Kir) channels of Aedes aegypti expressed in HEK cells and Xenopus oocytes, 2) inhibit the secretion of KCl but not NaCl in isolated Malpighian tubules, and after injection into the hemolymph, 3) inhibit KCl excretion in vivo, and 4) render mosquitoes flightless or dead within 24h. Some mosquitoes had swollen abdomens at death consistent with renal failure. VU625, the most potent and promising small molecule for development as mosquitocide, inhibits AeKir1-mediated currents with an IC50 less than 100 nM. It is highly selective for AeKir1 over mammalian Kir channels, and it affects only 3 of 68 mammalian membrane proteins. These results document 1) renal failure as a new mode-of-action for mosquitocide development, 2) renal Kir channels as molecular target for inducing renal failure, and 3) the promise of the discovery and development of new species-specific insecticides.
Keywords: Kir channels; Malpighian tubules; drug discovery; high throughput screen; insecticide; mosquitocide; renal failure; small molecules.