Use of β-Amino Acids in the Design of Substrate-Based Peptidase Inhibitors

  • R. A. Lew
  • E. Boulos
  • K. M. Stewart
  • P. Perlmutter
  • M. F. Harte
  • S. Bond
  • S. B. Reeve
  • M. U. Norman
  • M. J. Lew
  • M.-I. Aguilar
  • A. I. Smith
Part of the American Peptide Symposia book series (APSY, volume 7)

Abstract

ß-Amino acids contain an extra carbon between the amino and carboxy-termini; this modification renders the adjacent peptide bond resistant to hydrolysis [1,2]. We hypothesize that substitution of the residues at the scissile bond with ß-amino acids can confer resistance to cleavage without necessarily abolishing binding to the enzyme. In the present study, we have synthesized a series of ß-amino acid-substituted analogues of bradykinin (BK), and examined both their susceptibility to cleavage by and their ability to inhibit the soluble metalloendopeptidases EC 3.4.24.15 (EP24.15) and EC 3.4.24.16 (EP24.16) [3]. Our findings suggest that ß-amino acid incorporation at the scissile bond completely prevents peptide hydrolysis with only minimal reduction in affinity for the enzyme.

Keywords

Hydrolysis Bradykinin Thromboxane 

References

  1. 1.
    Hintermann, T., Seebach, D. Chimia 51, 244–247 (1997).Google Scholar
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    Seebach, D., Abele, S., Schreiber, I.V., Martinoni, B., Nussbaum, A.K., Schild, H., Schulz, H., Hennecke, H., Woessner, R., Bitsch, F. Chimia 52, 734–739 (1998).Google Scholar
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    Barrett, A.J., Brown, M.A., Dando, P.M., Knight, C.G., McKie, N., Rawlings, N.D., Serizawa, A. Methods Enzymol. 248, 529–556 (1995).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2001

Authors and Affiliations

  • R. A. Lew
    • 1
  • E. Boulos
    • 2
  • K. M. Stewart
    • 2
  • P. Perlmutter
    • 3
  • M. F. Harte
    • 3
  • S. Bond
    • 3
  • S. B. Reeve
    • 1
  • M. U. Norman
    • 1
  • M. J. Lew
    • 4
  • M.-I. Aguilar
    • 2
  • A. I. Smith
    • 1
  1. 1.Baker Medical Research InstituteMelbourneAustralia
  2. 2.Department of Biochemistry and Molecular BiologyMonash UniversityClaytonAustralia
  3. 3.Department of ChemistryMonash UniversityClaytonAustralia
  4. 4.Department of PharmacologyUniversity of MelbourneAustralia

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