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

Norbert Schaschke, Dominga Deluca, Irmgard Assfalg-Machleidt, Clara Höhneke, Christian P Sommerhoff, Werner Machleidt

Journal: Biological chemistry 2003;383(5):849-52

PMID: 12108551

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 cell-permeant should be useful tools to elucidate the effects of cathepsin B in the cytosol. We have covalently functionalised the poorly cell-permeant epoxysuccinyl-based cathepsin B inhibitor [R-Gly-Gly-Leu-(2S,3S)-tEps-Leu-Pro-OH; R=OMe] with the C-terminal heptapeptide segment of penetratin (R=epsilonAhx-Arg-Arg-Nle-Lys-Trp-Lys-Lys-NH2). 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 prodrug-like epoxysuccinyl peptides E64d and CA074Me.

Address: Max-Planck-Institut für Biochemie, Martinsried, Germany.

DOI: 10.1515/BC.2002.090

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MeSH Terms: Affinity Labels, Amino Acid Sequence, Carrier Proteins, Cathepsin B, Cathepsin L, Cathepsins, Cell Membrane Permeability, Cell-Penetrating Peptides, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Humans, Kinetics, Mammary Neoplasms, Experimental, Molecular Sequence Data, Oligopeptides, Peptide Fragments, Structure-Activity Relationship, Tumor Cells, Cultured