Novel Selective and Irreversible Mosquito Acetylcholinesterase Inhibitors for Controlling Malaria and Other Mosquito-Borne Diseases
Novel Selective and Irreversible Mosquito Acetylcholinesterase Inhibitors for Controlling Malaria and Other Mosquito-Borne Diseases
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DOI：
10.1038/srep01068
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发表时间：
2013-01-15
影响因子：
4.6
通讯作者：
Pang, Yuan-Ping
中科院分区：
文献类型：
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作者：
Dou, Dengfeng;Park, Jewn Giew;Pang, Yuan-Ping
我们以前报道过，昆虫乙酰胆碱酯酶（AChEs）可以选择性地和不可逆地抑制甲硫基磺酸酯推测通过共轭昆虫特异性半胱氨酸在这些酶。然而，迄今为止还没有关于缀合的直接证据，并且对于这种半胱氨酸靶向抑制剂是否具有用于杀虫剂用途的期望动力学性质仍然存在疑问。在这里，我们报告了质谱证据的共轭和新的化学物质，不可逆地抑制非洲疟疾蚊子AChE的双分子抑制速率常数（k（不起作用）/K-I）为3，604 - 458，597 M（-1）秒（-1），但幸免于人类AChE。相比之下，杀虫剂对氧磷在相同的测定条件下不可逆地抑制蚊子和人类乙酰胆碱酯酶，其k（非活性）/K-I值分别为1，915和1，507 M（-1）sec（-1）。这些结果进一步支持了我们的假设，即昆虫特异性乙酰胆碱酯酶半胱氨酸是一个独特的和未开发的目标，以开发新的杀虫剂，降低杀虫剂抗性和低毒性的哺乳动物，鱼类和鸟类的蚊媒疾病的控制。
We reported previously that insect acetylcholinesterases (AChEs) could be selectively and irreversibly inhibited by methanethiosulfonates presumably through conjugation to an insect-specific cysteine in these enzymes. However, no direct proof for the conjugation has been published to date, and doubts remain about whether such cysteine-targeting inhibitors have desirable kinetic properties for insecticide use. Here we report mass spectrometric proof of the conjugation and new chemicals that irreversibly inhibited African malaria mosquito AChE with bimolecular inhibition rate constants (k(inact)/K-I) of 3,604-458,597 M(-1)sec(-1) but spared human AChE. In comparison, the insecticide paraoxon irreversibly inhibited mosquito and human AChEs with k(inact)/K-I values of 1,915 and 1,507 M(-1)sec(-1), respectively, under the same assay conditions. These results further support our hypothesis that the insect-specific AChE cysteine is a unique and unexplored target to develop new insecticides with reduced insecticide resistance and low toxicity to mammals, fish, and birds for the control of mosquito-borne diseases.