Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, 13th Floor, Menara B, Persiaran MPAJ, Jalan Pandan Utama, Pandan Indah, 55100, Kuala Lumpur, Malaysia.
School of Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Sci Rep. 2017 Mar 27;7:45409. doi: 10.1038/srep45409.
The control of mosquitoes is threatened by the appearance of insecticide resistance and therefore new control chemicals are urgently required. Here we show that inhibitors of mosquito peptidyl dipeptidase, a peptidase related to mammalian angiotensin-converting enzyme (ACE), are insecticidal to larvae of the mosquitoes, Aedes aegypti and Anopheles gambiae. ACE inhibitors (captopril, fosinopril and fosinoprilat) and two peptides (trypsin-modulating oostatic factor/TMOF and a bradykinin-potentiating peptide, BPP-12b) were all inhibitors of the larval ACE activity of both mosquitoes. Two inhibitors, captopril and fosinopril (a pro-drug ester of fosinoprilat), were tested for larvicidal activity. Within 24 h captopril had killed >90% of the early instars of both species with 3 instars showing greater resistance. Mortality was also high within 24 h of exposure of 1, 2 and 3 instars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1 instars appeared to be less susceptible to this pro-drug even after 72 h exposure. Homology models of the larval An. gambiae ACE proteins (AnoACE2 and AnoACE3) reveal structural differences compared to human ACE, suggesting that structure-based drug design offers a fruitful approach to the development of selective inhibitors of mosquito ACE enzymes as novel larvicides.
蚊子的控制受到杀虫剂抗性出现的威胁，因此迫切需要新的控制化学品。在这里，我们表明蚊子肽二肽酶（一种与哺乳动物血管紧张素转换酶（ACE）相关的肽酶）的抑制剂对埃及伊蚊和冈比亚按蚊的幼虫具有杀虫作用。ACE 抑制剂（卡托普利、福辛普利和福辛普利酸）和两种肽（胰蛋白酶调节卵黄生成因子/TMOF 和缓激肽增效肽，BPP-12b）都是两种蚊子幼虫 ACE 活性的抑制剂。两种抑制剂，卡托普利和福辛普利（福辛普利酸的前药酯），都被测试了其杀幼虫活性。在 24 小时内，卡托普利杀死了两种物种的早期幼虫，超过 90%，而 3 龄幼虫的抗性更强。在接触福辛普利后 24 小时内，1、2 和 3 龄的冈比亚按蚊死亡率也很高。福辛普利对埃及伊蚊幼虫也有毒性，尽管 1 龄幼虫在 72 小时暴露后似乎对这种前药的敏感性较低。冈比亚按蚊幼虫 ACE 蛋白（AnoACE2 和 AnoACE3）的同源模型与人类 ACE 相比显示出结构差异，这表明基于结构的药物设计为开发作为新型杀幼虫剂的蚊子 ACE 酶的选择性抑制剂提供了一个有成效的方法。
