Omeprazole and its analogs exhibit insecticidal potencies as inhibitors of insect choline acetyltransferase

IF 4.2 1区 农林科学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jingting Wang, Tianye Hu, Xu He, Zhen Zhang, Na Yu, Zewen Liu
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Abstract

Choline acetyltransferase (ChAT) is crucial for acetylcholine synthesis and regulates diverse functions in numerous biological processes. Omeprazole, an inhibitor on human ChAT, was evaluated here on insect ChAT as a potential inhibitor, as well as its insecticidal potency on Nilaparvata lugens, a major insect pest on rice. The evaluation also included omeprazole analogs and α-NETA, in order to explore a superior leading compound targeting on insect ChAT. In toxicity test, α-NETA and omeprazole exhibited insecticidal activity, among which omeprazole exhibited activity with a mortality of around 50 % on N. lugens nymphs at 0.4 mg/mL. In vitro crude enzyme assays showed that omeprazole acted as an inhibitor on insect ChAT with a high selectivity and exciting potency compared with α-NETA and control. Three residues (Tyr84, Val95, Tyr589) was critical in N. lugens ChAT for interacting with its substrate choline through molecular docking, and it also revealed that omeprazole exhibited a higher binding affinity toward ChAT catalytic tunnel compared with α-NETA. Based on this, we screened omeprazole analogs for their affinity to N. lugens ChAT, and two compounds stood out. The 5-hydroxy omeprazole had the highest binding affinity by prediction, and 5-O-desmethyl omeprazole was with the lowest binding affinity. The toxicity bioassay and enzyme activity test were then performed on these two compounds. Aligned with the docking results, 5-hydroxy omeprazole showed a strong inhibitory effect and insecticidal activity. In summary, omeprazole and 5-hydroxy omeprazole could serve as lead compounds for insecticides targeting on insect ChAT, a novel target.

Abstract Image

奥美拉唑及其类似物作为昆虫胆碱乙酰转移酶抑制剂具有杀虫效力
胆碱乙酰转移酶(ChAT)对乙酰胆碱的合成至关重要,并在许多生物过程中调节多种功能。奥美拉唑是人类 ChAT 的一种抑制剂,本研究将其作为一种潜在的抑制剂,对昆虫 ChAT 及其对水稻上的一种主要害虫 Nilaparvata lugens 的杀虫效力进行了评估。评估还包括奥美拉唑类似物和 α-NETA,以探索一种针对昆虫 ChAT 的更优先导化合物。在毒性试验中,α-NETA 和奥美拉唑具有杀虫活性,其中奥美拉唑在 0.4 毫克/毫升的浓度下对 N. lugens 若虫的死亡率约为 50%。体外粗酶试验表明,奥美拉唑是昆虫 ChAT 的抑制剂,与 α-NETA 和对照组相比,具有高选择性和令人兴奋的效力。通过分子对接,发现奥美拉唑与底物胆碱的结合亲和力高于α-NETA。在此基础上,我们筛选了奥美拉唑类似物对 N. lugens ChAT 的亲和力,其中两个化合物脱颖而出。根据预测,5-羟基奥美拉唑的结合亲和力最高,5-O-去甲基奥美拉唑的结合亲和力最低。然后对这两种化合物进行了毒性生物测定和酶活性测试。与对接结果一致,5-羟基奥美拉唑具有很强的抑制作用和杀虫活性。综上所述,奥美拉唑和 5- 羟基奥美拉唑可作为针对昆虫 ChAT 这一新型靶标的杀虫剂先导化合物。
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来源期刊
CiteScore
7.00
自引率
8.50%
发文量
238
审稿时长
4.2 months
期刊介绍: Pesticide Biochemistry and Physiology publishes original scientific articles pertaining to the mode of action of plant protection agents such as insecticides, fungicides, herbicides, and similar compounds, including nonlethal pest control agents, biosynthesis of pheromones, hormones, and plant resistance agents. Manuscripts may include a biochemical, physiological, or molecular study for an understanding of comparative toxicology or selective toxicity of both target and nontarget organisms. Particular interest will be given to studies on the molecular biology of pest control, toxicology, and pesticide resistance. Research Areas Emphasized Include the Biochemistry and Physiology of: • Comparative toxicity • Mode of action • Pathophysiology • Plant growth regulators • Resistance • Other effects of pesticides on both parasites and hosts.
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