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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/208427
- author
- Wieczerzak, E
; Jankowska, E
; Rodziewicz-Motowidlo, S
; Gieldon, A
; Lagiewka, J
; Grzonka, Z
; Abrahamson, Magnus
LU
; Grubb, Anders
LU
and Bromme, D
- organization
- publishing date
- 2005
- 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
- 2016-04-01 16:37:43
- date last changed
- 2023-01-20 08:55:38
@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}},
keywords = {{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}},
doi = {{10.1111/j.1747-0285.2006.00329.x}},
volume = {{66}},
year = {{2005}},
}