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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, Nr. 5: S. 849-852


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.