Discovery and characterization of a potent and selective inhibitor of Aedes aegypti inward rectifier potassium channels.
Discovery and characterization of a potent and selective inhibitor of Aedes aegypti inward rectifier potassium channels.
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DOI：
10.1371/journal.pone.0110772
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Denton JS
中科院分区：
文献类型：
--
作者：
Raphemot R;Rouhier MF;Swale DR;Days E;Weaver CD;Lovell KM;Konkel LC;Engers DW;Bollinger SR;Hopkins C;Piermarini PM;Denton JS
由受感染的雌性蚊子传播的媒介传播疾病，如登革热和疟疾，影响着世界上近一半的人口。抗药性蚊子种群的出现正在降低传统杀虫剂的效力，并威胁到当前的媒介控制战略，这就迫切需要确定新的分子靶标，以针对新的杀虫剂类别进行开发。我们先前证明了哺乳动物KIR通道的小分子抑制剂是开发新的灭蚊剂的有前途的化学物质。在这项研究中，通过高通量筛选大约30,000个化学上不同的小分子来发现在HEK293细胞中异源表达的埃及伊蚊Kir1(AeKir1)通道的有效和选择性抑制剂。在283个已确认的筛选“HITS”中，基于其对AeKir1的效力和选择性以及药物化学的易处理性，小分子抑制剂VU625被选作先导优化和体内研究。在HEK293细胞的膜片钳电生理实验中，VU625抑制AeKir1的IC50值为96.8 nM，使VU625成为迄今描述的最有效的AeKir1抑制剂。此外，非洲爪哇卵母细胞的电生理实验表明，VU625是一种微弱的AeKir2B抑制剂。令人惊讶的是，注射VU625并没有对蚊子的行为、尿液排泄或存活率产生显著影响。然而，当与丙磺舒共注射时，VU625抑制蚊子的排泄能力，并具有毒性，表明该化合物是有机阴离子和/或ATP结合盒(ABC)转运体的底物。VU625(与丙磺舒联合注射)的剂量-毒性关系是双相的，这与VU625对AeKir1和AeKir2B具有不同效力的抑制分子相一致。这项研究证明了概念证明，可以使用传统的药物发现方法开发出有效和高选择性的蚊子KIR通道抑制剂。此外，它强化了这样一个概念，即决定化合物在体内的生物利用度的物理和化学性质将在确定KIR通道抑制剂作为杀虫剂的效力方面至关重要。
Vector-borne diseases such as dengue fever and malaria, which are transmitted by infected female mosquitoes, affect nearly half of the world's population. The emergence of insecticide-resistant mosquito populations is reducing the effectiveness of conventional insecticides and threatening current vector control strategies, which has created an urgent need to identify new molecular targets against which novel classes of insecticides can be developed. We previously demonstrated that small molecule inhibitors of mammalian Kir channels represent promising chemicals for new mosquitocide development. In this study, high-throughput screening of approximately 30,000 chemically diverse small-molecules was employed to discover potent and selective inhibitors of Aedes aegypti Kir1 (AeKir1) channels heterologously expressed in HEK293 cells. Of 283 confirmed screening ‘hits’, the small-molecule inhibitor VU625 was selected for lead optimization and in vivo studies based on its potency and selectivity toward AeKir1, and tractability for medicinal chemistry. In patch clamp electrophysiology experiments of HEK293 cells, VU625 inhibits AeKir1 with an IC50 value of 96.8 nM, making VU625 the most potent inhibitor of AeKir1 described to date. Furthermore, electrophysiology experiments in Xenopus oocytes revealed that VU625 is a weak inhibitor of AeKir2B. Surprisingly, injection of VU625 failed to elicit significant effects on mosquito behavior, urine excretion, or survival. However, when co-injected with probenecid, VU625 inhibited the excretory capacity of mosquitoes and was toxic, suggesting that the compound is a substrate of organic anion and/or ATP-binding cassette (ABC) transporters. The dose-toxicity relationship of VU625 (when co-injected with probenecid) is biphasic, which is consistent with the molecule inhibiting both AeKir1 and AeKir2B with different potencies. This study demonstrates proof-of-concept that potent and highly selective inhibitors of mosquito Kir channels can be developed using conventional drug discovery approaches. Furthermore, it reinforces the notion that the physical and chemical properties that determine a compound's bioavailability in vivo will be critical in determining the efficacy of Kir channel inhibitors as insecticides.
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影响因子：
11.8
作者：
Asidi A;N'Guessan R;Akogbeto M;Curtis C;Rowland M
通讯作者：
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