Kamal Mohammad A, Klein Peter, Yu Qian-Sheng, Tweedie David, Li Yazhou, Holloway Harold W, Greig Nigel H
Enzymoics, 7 Peterlee Pl., Hebersham, NSW 2770, Australia.
J Alzheimers Dis. 2006 Sep;10(1):43-51. doi: 10.3233/jad-2006-10108.
An explosion in the incidence of neurodegenerative diseases, particularly Alzheimer's disease (AD), is predicted in coming decades. Hence, the need to devise and assess new treatment strategies has never been more acute. AD, although an irreversible and progressive disorder, is currently treated with palliative, symptomatic therapy: primarily with acetylcholinesterase (AChE) inhibitors to amplify remaining cholinergic activity. New agents that, additionally, affect disease progression are sorely needed. Inhibition of brain butyrylcholinesterase (BuChE) represents a new drug target for AD treatment. Therefore, hand-in-hand with the development of selective ligands to inhibit BuChE in brain, it is fundamental to optimize assay conditions for kinetic studies of human BuChE. Kinetic analysis of serum BuChE, which is structurally similar to brain enzyme, was performed at dual substrate (butyrylthiocholine iodide) concentration ranges: 3-80 microM (low) and 25-800 microM (optimal) by use of the Ellman technique. Interaction of BuChE with a novel experimental AD therapeutic, bisnorcymserine (BNC; 0.06-2.0 nM) was also studied ex vivo. The IC_{50} and other key kinetic constants were determined for human serum BuChE inhibition by BNC, which proved to be a highly potent inhibitor in comparison to its structural analogue, cymserine. BNC may, additionally, lower the amyloid plaque-associated protein, amyloid-beta peptide. In synopsis, the characterization of the kinetic parameters of BuChE and BNC, described herein, is both aiding in the design of novel agents and optimizing their translation toward clinical use.
预计在未来几十年中，神经退行性疾病，尤其是阿尔茨海默病（AD）的发病率将大幅上升。因此，设计和评估新的治疗策略的需求从未如此迫切。AD虽然是一种不可逆的进行性疾病，但目前采用的是姑息性对症治疗：主要使用乙酰胆碱酯酶（AChE）抑制剂来增强剩余的胆碱能活性。迫切需要能够额外影响疾病进展的新药物。抑制脑丁酰胆碱酯酶（BuChE）是AD治疗的一个新的药物靶点。因此，在开发选择性配体以抑制脑中BuChE的同时，优化人BuChE动力学研究的测定条件至关重要。采用埃尔曼技术，在双底物（碘化硫代丁酰胆碱）浓度范围为3 - 80 microM（低）和25 - 800 microM（最佳）的条件下，对与脑酶结构相似的血清BuChE进行了动力学分析。还在体外研究了BuChE与一种新型实验性AD治疗药物双去甲环丝氨酸（BNC；0.06 - 2.0 nM）的相互作用。测定了BNC对人血清BuChE抑制作用的IC₅₀和其他关键动力学常数，与结构类似物环丝氨酸相比，BNC被证明是一种高效抑制剂。此外，BNC可能会降低与淀粉样斑块相关的蛋白β淀粉样肽。总之，本文所述的BuChE和BNC动力学参数的表征，既有助于新型药物的设计，也有助于优化其向临床应用的转化。
