Design and synthesis of inhibitors incorporating β-amino acids of metalloendopeptidase EC 3.4.24.15

David Steer, Rebecca Lew, Patrick P Perlmutter, Alexander Ian Smith, Mibel Aguilar

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27 Citations (Scopus)

Abstract

Endopeptidase EC 3.4.24.15 (EP 24.15) is a thermolysin-like metalloendopeptidase which is expressed widely throughout the body, with the highest concentrations in the brain, pituitary and testis. While the precise role of EP 24.15 remains unknown, it is thought to participate in the regulated metabolism of a number of specific neuropeptides. Of the limited number of inhibitors described for EP 24.15, N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-amino benzoate (CFP) is the most widely studied. CFP is a potent and specific inhibitor, but is unstable in vivo due to its cleavage between the alanine and tyrosine residues by the enzyme neprilysin (EP 24.11). The cpp-Ala-Ala N-terminal product of this cleavage is a potent inhibitor of angiotensin converting enzyme, which further limits the use of CFP in vivo. To generate specific inhibitors of EP 24.15 that are resistant to in vivo proteolysis by EP 24.11, β-amino acids have been incorporated into the structure of CFP. We have prepared racemic mixtures of β-amino acids containing proteogenic side chains, which are 9-fluorenylmethoxycarbonyl (Fmoc)-protected, and several analogues of CFP containing β-amino acids have been synthesized by solid phase peptide synthesis. The results of stability and inhibitory studies of these new analogues show that the incorporation of β-amino acids adjacent to the scissile bond can indeed stabilize the peptides against cleavage by EP 24.11 and still inhibit EP 24.15. The results obtained in these studies demonstrate the potential of these amino acids in the synthesis of peptidomimetics and in the design of new stable and specific therapeutics. Copyright (C) 2000 European Peptide Society and John Wiley and Sons, Ltd.

Original languageEnglish
Pages (from-to)470-477
Number of pages8
JournalJournal of Peptide Science
Volume6
Issue number9
DOIs
Publication statusPublished - 7 Oct 2000

Keywords

  • β-amino acid
  • Endopeptidase inhibitors
  • Metalloendeptidase EC3.4.24.15
  • Neprilysin

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