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Design and synthesis of tailored human caseinolytic protease P inhibitors

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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, T Cell, Hepatocyte, Cell Culture, Jurkat Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Thomas Gronauer

LAB HEAD: Stephan Axel Sieber

PROVIDER: PXD010277 | Pride | 2019-03-05

REPOSITORIES: Pride

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Design and synthesis of tailored human caseinolytic protease P inhibitors.

Gronauer Thomas F TF Mandl Melanie M MM Lakemeyer Markus M Hackl Mathias W MW Meßner Martina M Korotkov Vadim S VS Pachmayr Johanna J Sieber Stephan A SA

Chemical communications (Cambridge, England) 20180801 70

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 targ ...[more]

PMID: 30109319

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