Functional in vivo imaging of cysteine cathepsin activity in murine model of inflammation
Functional in vivo imaging of cysteine cathepsin activity in murine model of inflammation
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DOI：
10.1016/j.bmc.2010.10.028
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发表时间：
2011-02-01
影响因子：
3.5
通讯作者：
Wendt, K. Ulrich
中科院分区：
文献类型：
--
作者：
Caglic, Dejan;Globisch, Anja;Wendt, K. Ulrich
近红外荧光团(NIRF)标记的成像探针在生物分子成像应用中正变得越来越重要，即在肿瘤成像或炎症研究的动物模型中。在这项研究中，我们证明了先前引入的“反向设计”的化学概念代表了一种有效的策略，可以从经过化学优化的蛋白酶抑制剂中产生半胱氨酸蛋白酶的选择性探针，用于蛋白质组裂解产物的研究以及体内分子成像研究。新开发的基于活性的探针AW-091在体外被证明对组织蛋白酶S具有高度的选择性，并被证明在体内，即在酵母多糖诱导的小鼠炎症模型中，被证明是有用的半胱氨酸组织蛋白酶活性的监测。AW-091在更早的时间点显示出比市售的基于聚合物的ProSense680(Visen Medical)更高的信号与背景比，因此是研究导致各种疾病(包括炎症、癌症和类风湿性关节炎)的早期蛋白分解过程的有效新工具。此外，给予抗炎药地塞米松和组织蛋白酶抑制剂E-后，来自被切割的AW-091的荧光信号被减少，这为组织蛋白酶小分子抑制剂的评价提供了一个有价值的系统。(C)2010年由爱思唯尔有限公司出版。
Near-infrared fluorophore (NIRF)-labeled imaging probes are becoming increasingly important in bio-molecular imaging applications, that is, in animal models for tumor imaging or inflammation studies. In this study we showed that the previously introduced chemical concept of 'Reverse Design' represents an efficient strategy for the generation of selective probes for cysteine proteases from chemically optimized protease inhibitors for investigations in proteomic lysates as well as for in vivo molecular imaging studies. The newly developed activity-based probe AW-091 was demonstrated to be highly selective for cathepsin S in vitro and proved useful in monitoring cysteine cathepsin activity in vivo, that is, in zymosan-induced mouse model of inflammation. AW-091 showed higher signal-to-background ratios at earlier time points than the commercially available polymer-based ProSense680 (VisEn Medical) and thus represents an efficient new tool for studying early proteolytic processes leading to various diseases, including inflammation, cancer, and rheumatoid arthritis. In addition, the fluorescent signal originating from the cleaved AW-091 was shown to be reduced by the administration of an anti-inflammatory drug, dexamethasone and by the cathepsin inhibitor E-64, providing a valuable system for the evaluation of small-molecule inhibitors of cathepsins. (C) 2010 Published by Elsevier Ltd.