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Epoxysuccinyl peptide-derived cathepsin B inhibitors: Modulating membrane permeability by conjugation with the C- terminal heptapeptide segment of penetratin

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Schaschke,  N.
Moroder, Luis / Bioorganic Chemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Schaschke, N., Deluca, D., Assfalg-Machleidt, I., Höhneke, C., Sommerhoff, C. P., & Machleidt, W. (2002). Epoxysuccinyl peptide-derived cathepsin B inhibitors: Modulating membrane permeability by conjugation with the C- terminal heptapeptide segment of penetratin. Biological Chemistry, 383(5), 849-852.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0010-6F40-5
Abstract
Besides its physiological role in lysosomal protein breakdown, extralysosomal cathepsin B has recently been implicated in apoptotic cell death. Highly specific irreversible cathepsin B inhibitors that are readily cellpermeant should be useful tools to elucidate the effects of cathepsin B in the cytosol. We have covalently functionalised the poorly cellpermeant epoxysuccinyl based cathepsin B inhibitor [RGlyGlyLeu(2S, 3S)tEpsLeuProOH; R=OMe] with the Cterminal heptapeptide segment of penetratin (R=[epsilon]AhxArg ArgNleLysTrpLysLysNH(2)). The high inhibitory potency and selectivity for cathepsin B versus cathepsin L of the parent compound was not affected by the conjugation with the penetratin heptapeptide. The conjugate was shown to efficiently penetrate into MCF-7 cells as an active inhibitor, thereby circumventing an intracellular activation step that is required by other inhibitors, such as the prodruglike epoxysuccinyl peptides E64d and CA074Me.