Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with anti-fibrotic activity,Journal of the American Chemical Society

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Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with anti-fibrotic activity
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-06-24 , DOI: 10.1021/jacs.0c04527
Nattawadee Panyain ₁ , Aurélien Godinat ₁ , Thomas Lanyon-Hogg ₁ , Sofía Lachiondo-Ortega ₁ , Edward J Will ₁ , Christelle Soudy ₂ , Milon Mondal ₁ , Katie Mason ₃ , Sarah Elkhalifa ₃ , Lisa M Smith ₃ , Jeanine A Harrigan ₃ , Edward W Tate _{1,

2}

Affiliation

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitylating enzyme that is proposed as a potential therapeutic target in neurodegeneration, cancer, and liver and lung fibrosis. Herein we report the discovery of the most potent and selective UCHL1 probe (IMP-1710) to date based on a covalent inhibitor scaffold and apply this probe to identify and quantify target proteins in intact human cells. IMP-1710 stereoselectively labels the catalytic cysteine of UCHL1 at low nanomolar concentration in cells. We further demonstrate that potent and selective UCHL1 inhibitors block pro-fibrotic responses in a cellular model of idiopathic pulmonary fibrosis, supporting the potential of UCHL1 as a potential therapeutic target in fibrotic diseases.

中文翻译：

发现去泛素化酶 UCHL1 的有效选择性共价抑制剂和基于活性的探针，具有抗纤维化活性

泛素羧基末端水解酶 L1 (UCHL1) 是一种去泛素化酶，被提议作为神经退行性变、癌症、肝纤维化和肺纤维化的潜在治疗靶点。在此，我们报告了迄今为止基于共价抑制剂支架的最有效和选择性的 UCHL1 探针 (IMP-1710) 的发现，并应用该探针来识别和量化完整人类细胞中的靶蛋白。 IMP-1710 在细胞中以低纳摩尔浓度立体选择性地标记 UCHL1 的催化半胱氨酸。我们进一步证明，有效且选择性的 UCHL1 抑制剂可阻断特发性肺纤维化细胞模型中的促纤维化反应，支持 UCHL1 作为纤维化疾病潜在治疗靶点的潜力。

更新日期：2020-06-24

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