洛哌丁胺的抗生素作用:洛哌丁胺人靶点与棘阿米巴原虫靶点的同源性。

Q3 Medicine
Abdul M Baig, Zohaib Rana, Mohsin Mannan, Sumayya Tariq, H R Ahmad
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引用次数: 7

摘要

背景:洛哌丁胺是一种用于非感染性腹泻的抗腹泻药物。该药是一种阿片受体激动剂、电压依赖性钙通道(Cav)阻滞剂和钙调素(CaM)抑制剂。据报道,洛哌丁胺对卡斯特兰棘阿米巴致病性菌株具有抗阿米巴作用。目的:尚不清楚洛哌丁胺致棘阿米巴细胞死亡的确切作用方式、与人对应物的细胞靶点同源性和模式。此外,我们试图在棘阿米巴中建立一个原始洞穴的存在。方法:本研究采用生物信息学、三维结构建模、配体结合预测和凋亡/杀阿米巴实验来回答上述问题。比较了人类和castellanii参与钙(Ca+2)稳态调节的蛋白的氨基酸序列和结构模型。结果:我们的研究结果表明,A. castellanii表达类似的,几乎相同类型的原始钙通道Cav Ac和CaM,这是洛哌丁胺在人类中众所周知的靶点。生长试验显示不同剂量的洛哌丁胺抗阿米巴作用,无论是单独使用还是与其他Ca+2- CaM抑制剂联合使用。洛哌丁胺与氟哌啶醇的协同作用比单独使用时更有杀阿米巴的作用。Annexin V、吖啶橙和碘化丙啶成像显示,剂量为100µg/ml时,castellanii细胞凋亡,较高剂量为250µg/ml时出现坏死。结论:棘阿米巴不表达人类mu-阿片受体的同源物,但有证据表明洛哌胺其他已知的人类靶点的同源物参与Ca+2摄取和Ca+2信号转导途径。这表明,优化与这些靶点的类似药物相互作用,可能有助于开发新的方法来控制这种寄生虫的生长,并可能控制由它引起的疾病。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Antibiotic Effects of Loperamide: Homology of Human Targets of Loperamide with Targets in Acanthamoeba spp.

Background: Loperamide is an anti-diarrheal drug prescribed for non-infectious diarrhea. The drug is an opioid receptor agonist, blocker of voltage-dependent calcium channel (Cav) and calmodulin (CaM) inhibitor on human cells. Loperamide has been reported to exert anti-amoebic effects against pathogenic strains of Acanthamoeba castellanii.

Objectives: The precise mode of antibiotic action, cellular target homology with human counterparts and the pattern of cell death induced by loperamide in Acanthamoeba castellanii remain to be established. Additionally, we attempt to establish the presence a primitive Cav in Acanthamoeba castellanii.

Methods: Bioinformatics, 3D structural modelling, ligand binding predictions and apoptotic/ amoebicidal assays were used in this study to answer the above queries. Amino acid sequences and structural models were compared between human and A. castellanii proteins that are involved in the regulation of calcium (Ca+2) homeostasis.

Results: Our results show that A. castellanii expresses similar, to near identical types of primitive calcium channels Cav Ac and CaM that are well known targets of loperamide in humans. The growth assays showed anti-amoebic effects of loperamide at different doses, both alone and in combinations with other Ca+2- CaM inhibitors. The synergistic actions of loperamide with haloperidol showed to be more amoebicidal than when either of them used alone. Imaging with Annexin V, Acridine orange and Propidium iodide showed apoptosis in A. castellanii at a dose of 100 µg/ml and necrosis at higher doses of 250 µg/ml.

Conclusion: Though, Acanthamoeba does not express a homolog of the human mu-opioid receptor, but does shows evidence of the homologs for other known human targets of loperamide that are involved in Ca+2 uptake and Ca+2 signal transduction pathways. This suggests optimization of similar drug interactions with these targets may be useful in developing new approaches to control the growth of this parasite and possibly the diseases caused by it.

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来源期刊
Recent patents on anti-infective drug discovery
Recent patents on anti-infective drug discovery Medicine-Pharmacology (medical)
CiteScore
2.40
自引率
0.00%
发文量
1
期刊介绍: Recent Patents on Anti-Infective Drug Discovery publishes review articles on recent patents in the field of anti-infective drug discovery e.g. novel bioactive compounds, analogs & targets. A selection of important and recent patents on anti-infective drug discovery is also included in the journal. The journal is essential reading for all researchers involved in anti-infective drug design and discovery.
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