Cell penetrable, clickable and tagless activity-based probe of human cathepsin L
Cell penetrable, clickable and tagless activity-based probe of human cathepsin L
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DOI：
10.1016/j.bioorg.2019.02.032
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发表时间：
2019-04-01
影响因子：
5.1
通讯作者：
Pathak, Sanjai K.
中科院分区：
文献类型：
--
作者：
Dana, Dibyendu;Garcia, Jeremy;Pathak, Sanjai K.
人组织蛋白酶L是一种普遍表达的内肽酶，在多种细胞信号转导事件中发挥关键作用。它的过度表达与许多人类疾病有关，包括高度侵袭性的癌症。因此，组织蛋白酶L的抑制被认为是一种可行的治疗策略。不幸的是，最近出现了几个冗余甚至相反的组织蛋白酶L的作用。因此，在将大量资源用于药物发现工作之前，需要选择性组织蛋白酶L探针以特定环境的方式剖析其功能。本文报道了一种可点击且无标签的组织蛋白酶L活性探针的开发。该探针具有高效、活性位点定向和活性依赖、选择性、细胞穿透性和对人体细胞无毒的特点。通过斑马鱼模型，我们证明了探针在斑马鱼孵化过程中可以抑制体内组织蛋白酶L的功能。预计该探针将成为在正常生理和人类疾病的蛋白质组水平上解剖组织蛋白酶L生物学的高效工具，从而促进针对组织蛋白酶L的药物发现工作。
Human cathepsin L is a ubiquitously expressed endopeptidase and is known to play critical roles in a wide variety of cellular signaling events. Its overexpression has been implicated in numerous human diseases, including highly invasive forms of cancer. Inhibition of cathepsin L is therefore considered a viable therapeutic strategy. Unfortunately, several redundant and even opposing roles of cathepsin L have recently emerged. Selective cathepsin L probes are therefore needed to dissect its function in context-specific manner before significant resources are directed into drug discovery efforts. Herein, the development of a clickable and tagless activity-based probe of cathepsin L is reported. The probe is highly efficient, active-site directed and activity-dependent, selective, cell penetrable, and non-toxic to human cells. Using zebrafish model, we demonstrate that the probe can inhibit cathepsin L function in vivo during the hatching process. It is anticipated that the probe will be a highly effective tool in dissecting cathepsin L biology at the proteome levels in both normal physiology and human diseases, thereby facilitating drug-discovery efforts targeting cathepsin L.