Brain butyrylcholinesterase (BChE) is an attractive target for drugs designed for the treatment of Alzheimer's disease (AD) in its advanced stages. It also potentially represents a biomarker for progression of this disease. Based on the crystal structure of previously described highly potent, reversible, and selective BChE inhibitors, we have developed the fluorescent probes that are selective towards human BChE. The most promising probes also maintain their inhibition of BChE in the low nanomolar range with high selectivity over acetylcholinesterase. Kinetic studies of probes reveal a reversible mixed inhibition mechanism, with binding of these fluorescent probes to both the free and acylated enzyme. Probes show environment-sensitive emission, and additionally, one of them also shows significant enhancement of fluorescence intensity upon binding to the active site of BChE. Finally, the crystal structures of probes in complex with human BChE are reported, which offer an excellent base for further development of this library of compounds.

中文翻译：

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开发丁酰胆碱酯酶的有效可逆选择性抑制剂作为荧光探针。

脑丁酰胆碱酯酶（BChE）是设计用于治疗晚期阿尔茨海默氏病（AD）的药物的有吸引力的靶标。它还可能代表该疾病进展的生物标记。基于先前描述的高效，可逆和选择性BChE抑制剂的晶体结构，我们开发了对人BChE具有选择性的荧光探针。最有希望的探针还可以在低纳摩尔范围内保持对BChE的抑制作用，并且对乙酰胆碱酯酶的选择性高。探针的动力学研究揭示了可逆的混合抑制机制，这些荧光探针与游离酶和酰化酶结合。探针显示对环境敏感的辐射，此外，其中之一还显示出与BChE活性位点结合后荧光强度显着增强。最后，报道了与人BChE结合的探针的晶体结构，为进一步开发该化合物库提供了极好的基础。