Beyenbach Klaus W, Yu Yasong, Piermarini Peter M, Denton Jerod
Department of Biomedical Sciences; Cornell University ; Ithaca, NY USA.
College of Medicine; SUNY Downstate Medical Center ; Brooklyn, NY USA.
Tissue Barriers. 2015 Sep 1;3(4):e1081861. doi: 10.1080/21688370.2015.1081861. eCollection 2015 Oct-Dec.
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.
在高通量筛选中鉴定出三种小分子，它们能够：1）阻断在人胚肾细胞（HEK细胞）和非洲爪蟾卵母细胞中表达的埃及伊蚊肾脏内向整流钾通道（Kir）；2）抑制离体马氏管中氯化钾而非氯化钠的分泌，且在注入血淋巴后，3）抑制体内氯化钾的排泄；4）使蚊子在24小时内无法飞行或死亡。一些蚊子死亡时腹部肿胀，这与肾衰竭相符。VU625是作为灭蚊剂开发最有效且最具潜力的小分子，它抑制AeKir1介导的电流，半数抑制浓度（IC50）小于100纳摩尔。它对AeKir1的选择性远高于哺乳动物的Kir通道，并且仅影响68种哺乳动物膜蛋白中的3种。这些结果证明：1）肾衰竭是灭蚊剂开发的一种新作用方式；2）肾脏Kir通道是诱导肾衰竭的分子靶点；3）发现和开发新的物种特异性杀虫剂具有前景。
