title: Epoxysuccinyl peptide-derived cathepsin B inhibitors: modulating membrane permeability by conjugation with the C-terminal heptapeptide segment of penetratin.
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.
authors.affiliation: Max-Planck-Institut für Biochemie, Martinsried, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Schaschke
authors.forename: Dominga
authors.initials: D
authors.lastname: Deluca
authors.forename: Irmgard
authors.initials: I
authors.lastname: Assfalg-Machleidt
authors.forename: Clara
authors.initials: C
authors.lastname: Höhneke
authors.forename: Christian P
authors.initials: CP
authors.lastname: Sommerhoff
authors.forename: Werner
authors.initials: W
authors.lastname: Machleidt
mesh_terms: D000345:Affinity Labels / Q000138:chemical synthesis / Q000737:chemistry; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002463:Cell Membrane Permeability; D057846:Cell-Penetrating Peptides; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
chemical_list: D000345:Affinity Labels; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; C414409:penetratin; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L