摘要
在疟疾死亡率大大降低了在过去的15年中已经完成,部分是由于广泛推出的杀虫剂处理过的蚊帐在非洲撒哈拉以南地区。到目前为止,这些蚊帐仅使用拟除虫菊酯,杀虫剂的目标电压门控钠离子通道的疟疾媒介,Anopheles gambiae。由于A。冈比亚有抗药性的菌株拟除虫菊酯,有开发新的公共卫生杀虫剂,搞一个不同的目标,具有低毒的迫切需要。在本文中,我们将描述努力发展高度物种特异性和抗性突破抑制剂。冈比亚乙酰胆碱酯酶(Agache)。这些工作在酶的结构知识方面的进步得到了极大的帮助,和两个主要的抑制剂的设计策略进行了有益的探索。由于具有未配对Agache Cys残基不是哺乳动物乙酰胆碱酯酶,实现选择性抑制的逻辑策略包括的化合物,可以结扎,Cys的设计。第二种策略是设计新的分子来靶向酶的催化丝氨酸。这里的挑战是不仅要实现高INH抑制的选择性与人类的疼痛,而且还表明毒性的。冈比亚携带耐药突变的g119s Agache。将提出的进展和面临的挑战。THIs审查是“杀虫剂作用方式:从昆虫到哺乳动物毒性的特别问题”的一部分。
关键词: Acetylcholinesterase,巯基试剂、胱氨酸、氨基甲酸酯、甲基酮、二氟甲基酮..
Current Medicinal Chemistry
Title:Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito
Volume: 24 Issue: 27
关键词: Acetylcholinesterase,巯基试剂、胱氨酸、氨基甲酸酯、甲基酮、二氟甲基酮..
摘要: Great reductions in malaria mortality have been accomplished in the last 15 years, in part due to the widespread roll-out of insecticide-treated bednets across sub-Saharan Africa. To date, these nets only employ pyrethroids, insecticides that target the voltage-gated sodium ion channel of the malaria vector, Anopheles gambiae. Due to the growing emergence of An. gambiae strains that are resistant to pyrethroids, there is an urgent need to develop new public health insecticides that engage a different target and possess low mammalian toxicity. In this review, we will describe efforts to develop highly species-specific and resistance-breaking inhibitors of An. gambiae acetylcholinesterase (AgAChE). These efforts have been greatly aided by advances in knowledge of the structure of the enzyme, and two major inhibitor design strategies have been explored. Since AgAChE possesses an unpaired Cys residue not present in mammalian AChE, a logical strategy to achieve selective inhibition involves design of compounds that could ligate that Cys. A second strategy involves the design of new molecules to target the catalytic serine of the enzyme. Here the challenge is not only to achieve high inhibition selectivity vs human AChE, but also to demonstrate toxicity to An. gambiae that carry the G119S resistance mutation of AgAChE. The advances made and challenges remaining will be presented. This review is part of the special issue "Insecticide Mode of Action: From Insect to Mammalian Toxicity.
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Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito, Current Medicinal Chemistry 2017; 24 (27) . https://dx.doi.org/10.2174/0929867324666170206130024
DOI https://dx.doi.org/10.2174/0929867324666170206130024 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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