Crystal structures of angiotensin-converting enzyme from Anopheles gambiae in its native form and with a bound inhibitor
Crystal structures of angiotensin-converting enzyme from Anopheles gambiae in its native form and with a bound inhibitor
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DOI：
10.1042/bcj20190635
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发表时间：
2019-11-01
影响因子：
4.1
通讯作者：
Acharya, K. Ravi
中科院分区：
文献类型：
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作者：
Cashman, John S.;Cozier, Gyles E.;Acharya, K. Ravi
按蚊和伊蚊属的蚊子是对人类最致命的昆虫之一，因为它们作为疟疾和一系列虫媒病毒的有效载体，包括黄热病，登革热，基孔肯雅病，西尼罗河和寨卡病毒。使用不同化学类别的杀虫剂是防治按蚊综合战略的关键组成部分。gambiae和Ae.但杀虫剂抗药性问题意味着迫切需要具有不同作用模式的新化合物来取代无法控制抗药性蚊子种群的化学品。我们以前已经表明，饲养肽基二肽酶A的抑制剂，以两个An。gambiae和Ae.埃及蚊幼虫导致发育不良和死亡。然而，这些化合物被设计为抑制哺乳动物形式的酶（血管紧张素转化酶，ACE），因此可能具有较低的效力并且缺乏作为昆虫肽酶抑制剂的选择性。因此，为了开发在杀死蚊子幼虫方面具有实用价值的抑制剂，重要的是设计既有效又具有高度选择性的新化合物。在这里，我们报告了来自An的AnoACE 2的第一个结构。以其天然形式的冈比亚红血球和与结合的人ACE抑制剂福辛普利拉。将这些结构与人ACE（sACE）和来自黑腹果蝇（Drosophila melanogaster）的昆虫ACE同源物（AnCE）进行比较，发现AnoACE2结构与AnCE更相似。此外，这些结构不同的重要元素提供了可能用于设计选择性杀蚊剂开发的化学先导物的信息。
The mosquitoes of the Anopheles and Aedes genus are some of the most deadly insects to humans because of their effectiveness as vectors of malaria and a range of arbo-viruses, including yellow fever, dengue, chikungunya, West Nile and Zika. The use of insecticides from different chemical classes is a key component of the integrated strategy against An. gambiae and Ae. aegypti, but the problem of insecticide resistance means that new compounds with different modes of action are urgently needed to replace chemicals that fail to control resistant mosquito populations. We have previously shown that feeding inhibitors of peptidyl dipeptidase A to both An. gambiae and Ae. aegypti mosquito larvae lead to stunted growth and mortality. However, these compounds were designed to inhibit the mammalian form of the enzyme (angiotensin-converting enzyme, ACE) and hence can have lower potency and lack selectivity as inhibitors of the insect peptidase. Thus, for the development of inhibitors of practical value in killing mosquito larvae, it is important to design new compounds that are both potent and highly selective. Here, we report the first structures of AnoACE2 from An. gambiae in its native form and with a bound human ACE inhibitor fosinoprilat. A comparison of these structures with human ACE (sACE) and an insect ACE homologue from Drosophila melanogaster (AnCE) revealed that the AnoACE2 structure is more similar to AnCE. In addition, important elements that differ in these structures provide information that could potentially be utilised in the design of chemical leads for selective mosquitocide development.