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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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Norbert Schaschke
Published/Copyright:
June 1, 2005
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=AhxArg ArgNleLysTrpLysLysNH2). 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.
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Published Online: 2005-06-01
Published in Print: 2002-05-15
Copyright © 2002 by Walter de Gruyter GmbH & Co. KG
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Articles in the same Issue
- Nobuhiko Katunuma: An Outstanding Scientific and Professional Career of a Warm-Hearted Person. Reflections on the Occasion of his 75th Birthday
- Structural and Functional Diversity of Connexin Genes in the Mouse and Human Genome
- Congopain from Trypanosoma congolense: Drug Target and Vaccine Candidate
- Biosynthesis of Lysosomal Proteinases in Health and Disease
- Calpain Function in the Differentiation of Mesenchymal Stem Cells
- Ku Antigen Supports Termination of Mammalian rDNA Replication by Transcription Termination Factor TTF-I
- Thyroid Stimulating Hormone Upregulates Secretion of Cathepsin B from Thyroid Epithelial Cells
- Selective Release of Calpain Produced αII-Spectrin (α-Fodrin) Breakdown Products by Acute Neuronal Cell Death
- Altered Storage of Proteases in Mast Cells from Mice Lacking Heparin: A Possible Role for Heparin Carboxypeptidase A Processing
- Clustering-Induced Signaling of CEACAM1 in PC12 Cells
- Spin Adducts of Superoxide, Alkoxyl, and Lipid-Derived Radicals with EMPO and Its Derivatives
- Glutathione S-Transferase of the Malarial Parasite Plasmodium falciparum: Characterization of a Potential Drug Target
- Analysis of the Structural Determinants for RNA Binding of the Human Protein AUF1/hnRNP D
- Effect of Cysteine Proteinase Inhibitors on Murine B16 Melanoma Cell Invasion in vitro
- Stage-Specific Antimalarial Activity of Cysteine Protease Inhibitors
- Epoxysuccinyl Peptide-Derived Cathepsin B Inhibitors: Modulating Membrane Permeability by Conjugation with the C-Terminal Heptapeptide Segment of Penetratin
- Design of Inhibitors for Human Tissue Kallikrein Using Non-Natural Aromatic and Basic Amino Acids
- Amyloid Fibril Formation by Human Stefin B in vitro: Immunogold Labelling and Comparison to Stefin A
- Lysosomal Peptidases and Glycosidases in Rheumatoid Arthritis
