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Discovery of Fluoromethylketone-based Peptidomimetics as Covalent ATG4B (autophagin-1) Inhibitors.

ACS Med Chem Lett.. 2016-08;

Qiu Z, Kuhn B, Aebi J, Lin X, Ding H, Zhou Z, Xu Z, Xu D, Han L, Liu C, Qiu H, Zhang Y, Haap W, Riemer C, Stahl M, Qin N, Shen HC, Tang G.

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Abstract

ATG4B or autophagin-1 is a cysteine protease that cleaves ATG8 family proteins. ATG4B plays essential roles in the autophagosome formation and the autophagy pathway. Herein we disclose the design and structural modifications of a series of fluoromethylketone (FMK)-based peptidomimetics as highly potent ATG4B inhibitors. Their structure-activity relationship (SAR) and protease selectivity are also discussed.

Keywords

ATG4B; autophagy; covalent inhibitor; fluoromethylketone; peptidomimetics

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