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Substrate/propeptide-derived endo-epoxysuccinyl peptides as highly potent and selective cathepsin B inhibitors



Substrate/propeptide-derived endo-epoxysuccinyl peptides as highly potent and selective cathepsin B inhibitors



FEBS Letters 421(1): 80-82



Based on recent information about the anti-substrate binding mode of the propeptide portion of procathepsin B and the well established substrate-like binding of epoxysuccinyl-dipeptide carboxylates to the S' subsites of cathepsin B a new endo-trans-epoxysuccinyl peptide was synthesized that contains the dipeptide moiety Leu-Pro-OH for the P1'-P2' substrate positions and the tripeptide moiety Leu-Gly-Gly-OMe (sequence portion 46-48 of the propeptide) for the P2-P4 positions in anti-substrate orientation. With an unequivocal (2S,3S) configuration this new trans-epoxysuccinyl peptide derivative was found to inhibit cathepsin B with an apparent second-order rate constant of 1,520,000 M(-1) s(-1) which represents so far the most potent inhibitor among E-64-derived compounds. Conversely, the (2R,3R) diastereomer exhibited a significantly lower inhibition potency. This observation fully agrees with our previous findings that inhibitor/enzyme interactions at the S subsites are favored by the (2S,3S) and reverse interactions at the S' subsites by the (2R,3R) configuration of the trans-epoxysuccinyl moiety.

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Accession: 009485808

Download citation: RISBibTeXText

PMID: 9462845

DOI: 10.1016/s0014-5793(97)01538-x


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