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Design and synthesis of tailored human caseinolytic protease P inhibitors

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Abstract

Human caseinolytic protease P (hClpP) is important for degradation of misfolded proteins in the mitochondrial unfolded protein response. We here introduce tailored hClpP inhibitors that utilize a steric discrimination in their core naphthofuran scaffold to selectively address the human enzyme. This novel inhibitor generation exhibited superior activity compared to previously introduced beta-lactones, optimized for bacterial ClpP. Further insights into the bioactivity and binding to cellular targets were obtained via chemical proteomics as well as proliferation- and migration studies in cancer cells.

Graphical abstract: Design and synthesis of tailored human caseinolytic protease P inhibitors

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Publication details

The article was received on 30 Jun 2018, accepted on 02 Aug 2018 and first published on 02 Aug 2018


Article type: Communication
DOI: 10.1039/C8CC05265D
Citation: Chem. Commun., 2018, Advance Article
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    Design and synthesis of tailored human caseinolytic protease P inhibitors

    T. F. Gronauer, M. M. Mandl, M. Lakemeyer, M. W. Hackl, M. Meßner, V. S. Korotkov, J. Pachmayr and S. A. Sieber, Chem. Commun., 2018, Advance Article , DOI: 10.1039/C8CC05265D

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