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

E Wieczerzak, E Jankowska, S Rodziewicz-Motowidlo, A Gieldon, J Lagiewka, Z Grzonka, Magnus Abrahamson, Anders Grubb, D Bromme

Research output: Contribution to journalArticlepeer-review

12 Citations (SciVal)

Abstract

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.
Original languageEnglish
Pages (from-to)1-11
JournalJournal of Peptide Research
Volume66
Issue numberS1
DOIs
Publication statusPublished - 2005

Subject classification (UKÄ)

  • Pharmacology and Toxicology
  • Medicinal Chemistry

Keywords

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

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