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Discovery and Development of TMPRSS6 Inhibitors Modulating Hepcidin Levels in Human Hepatocytes.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-09-19 , DOI: 10.1016/j.chembiol.2019.09.004 François Béliveau 1 , Aarti Tarkar 2 , Sébastien P Dion 1 , Antoine Désilets 1 , Mariana Gabriela Ghinet 1 , Pierre-Luc Boudreault 1 , Catherine St-Georges 1 , Éric Marsault 1 , Daniel Paone 2 , Jon Collins 2 , Colin H Macphee 2 , Nino Campobasso 3 , Arthur Groy 3 , Josh Cottom 3 , Michael Ouellette 3 , Andrew J Pope 2 , Richard Leduc 1
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-09-19 , DOI: 10.1016/j.chembiol.2019.09.004 François Béliveau 1 , Aarti Tarkar 2 , Sébastien P Dion 1 , Antoine Désilets 1 , Mariana Gabriela Ghinet 1 , Pierre-Luc Boudreault 1 , Catherine St-Georges 1 , Éric Marsault 1 , Daniel Paone 2 , Jon Collins 2 , Colin H Macphee 2 , Nino Campobasso 3 , Arthur Groy 3 , Josh Cottom 3 , Michael Ouellette 3 , Andrew J Pope 2 , Richard Leduc 1
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Iron overload disorders are characterized by the body's inability to regulate iron absorption and its storage which can lead to organ failures. Accumulated evidence has revealed that hepcidin, the master regulator of iron homeostasis, is negatively modulated by TMPRSS6 (matriptase-2), a liver-specific type II transmembrane serine protease (TTSP). Here, we report that treatment with a peptidomimetic inhibitor affecting TMPRSS6 activity increases hepcidin production in hepatic cells. Moreover, similar effects were observed when using non-peptidic inhibitors obtained through optimization of hits from high-throughput screening. Using HepG2 cells and human primary hepatocytes, we show that TMPRSS6 inhibitors block TMPRSS6-dependent hemojuvelin cleavage and increase HAMP expression and levels of secreted hepcidin.
中文翻译：
调节人肝细胞中铁调素水平的TMPRSS6抑制剂的发现和开发。
铁超负荷疾病的特征在于人体无法调节铁的吸收及其储存，这可能导致器官衰竭。越来越多的证据表明，铁稳态的主要调节剂铁调素被肝脏特异性的II型跨膜丝氨酸蛋白酶TMPRSS6（matriptase-2）负调节。在这里，我们报告用影响TMPRSS6活性的拟肽抑制剂治疗增加了肝细胞中铁调素的产生。此外，当使用通过优化高通量筛选的命中率获得的非肽类抑制剂时，观察到了相似的效果。使用HepG2细胞和人类原代肝细胞，我们显示TMPRSS6抑制剂可阻断TMPRSS6依赖性的血枣素裂解，并增加HAMP表达和分泌的铁调素水平。
更新日期：2019-11-09
中文翻译：
调节人肝细胞中铁调素水平的TMPRSS6抑制剂的发现和开发。
铁超负荷疾病的特征在于人体无法调节铁的吸收及其储存，这可能导致器官衰竭。越来越多的证据表明，铁稳态的主要调节剂铁调素被肝脏特异性的II型跨膜丝氨酸蛋白酶TMPRSS6（matriptase-2）负调节。在这里，我们报告用影响TMPRSS6活性的拟肽抑制剂治疗增加了肝细胞中铁调素的产生。此外，当使用通过优化高通量筛选的命中率获得的非肽类抑制剂时，观察到了相似的效果。使用HepG2细胞和人类原代肝细胞，我们显示TMPRSS6抑制剂可阻断TMPRSS6依赖性的血枣素裂解，并增加HAMP表达和分泌的铁调素水平。
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