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Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B

In English

Författare

Summary, in English

We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor-enzyme complex, K-i, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z-Arg-Leu-His-Agly-Ile-Val-OMe (7) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7. We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K.

Publiceringsår

2005

Språk

Engelska

Sidor

1-11

Publikation/Tidskrift/Serie

Journal of Peptide Research

Volym

66

Issue

S1

Dokumenttyp

Artikel i tidskrift

Förlag

Wiley-Blackwell

Ämne

  • Pharmacology and Toxicology
  • Medicinal Chemistry

Nyckelord

  • cysteine protease inhibitors
  • cathepsin K
  • azapeptide
  • cathepsin B
  • peptidomimetic

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1397-002X