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

Wieczerzak, E; Jankowska, E; Rodziewicz-Motowidlo, S; Gieldon, A; Lagiewka, J; Grzonka, Z; Abrahamson, Magnus LU ; Grubb, Anders LU and Bromme, D (2005) In Journal of Peptide Research 66(S1). p.1-11
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.... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cysteine protease inhibitors, cathepsin K, azapeptide, cathepsin B, peptidomimetic
in
Journal of Peptide Research
volume
66
issue
S1
pages
1 - 11
publisher
Wiley-Blackwell
external identifiers
  • wos:000237420500001
  • scopus:33645067621
ISSN
1397-002X
DOI
10.1111/j.1747-0285.2006.00329.x
language
English
LU publication?
yes
id
732cc211-2044-4f1d-b229-d36f33873451 (old id 208427)
date added to LUP
2007-08-20 15:38:02
date last changed
2017-08-06 04:36:09
@article{732cc211-2044-4f1d-b229-d36f33873451,
  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.},
  author       = {Wieczerzak, E and Jankowska, E and Rodziewicz-Motowidlo, S and Gieldon, A and Lagiewka, J and Grzonka, Z and Abrahamson, Magnus and Grubb, Anders and Bromme, D},
  issn         = {1397-002X},
  keyword      = {cysteine protease inhibitors,cathepsin K,azapeptide,cathepsin B,peptidomimetic},
  language     = {eng},
  number       = {S1},
  pages        = {1--11},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Peptide Research},
  title        = {Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B},
  url          = {http://dx.doi.org/10.1111/j.1747-0285.2006.00329.x},
  volume       = {66},
  year         = {2005},
}