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

Schaschke, Norbert; Deluca, Dominga; Assfalg-Machleidt, Irmgard; Höhneke, Clara; Sommerhoff, Christian P. und Machleidt, Werner (2002): Epoxysuccinyl peptide-derived cathepsin B inhibitors: Modulating membrane permeability by conjugation with the C-terminal heptapeptide segment of penetratin. In: Biological Chemistry, Vol. 383, No. 5: pp. 849-852

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 C-terminal heptapeptide segment of penetratin (R=εAhxArg 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.

• Item Type: Journal article
• Form of publication: Publisher's Version
• Faculties: Medicine
• Subjects: 500 Science > 540 Chemistry
• ISSN: 1431-6730
• Alliance/National Licence: This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
• Language: English