Azapeptides structurally based upon inhibitory sites of cystatins as potent and selective inhibitors of cysteine proteases
Wieczerzak, Ewa LU ; Drabik, P ; Lankiewicz, L ; Oldziej, S ; Grzonka, Z ; Abrahamson, Magnus LU ; Grubb, Anders LU
and Bromme, D
(2002)
In Journal of Medicinal Chemistry
45(19).
p.4202-4211
- Abstract
- A series of azapeptides as potential inhibitors of cysteine proteases were synthesized. Their structures, based on the binding center of cystatins, contain an azaglycine residue (Agly) in place of the evolutionarily conserved glycine residue in the N-terminal part of the enzyme binding region of cystatins. Incorporation of Agly should lead to deactivation of the acyl-enzyme complex formed against nucleophilic attack by water molecules in the final step of peptide bond hydrolysis. The majority of synthesized azapeptides shows high inhibitory potency toward the investigated cysteine proteases, papain, cathepsin B, and cathepsin K. One of them, Z-Arg-Leu-Val-Agly-Ile-Val-OMe (compound 17), which contains in its sequence the amino acid... (More)
- A series of azapeptides as potential inhibitors of cysteine proteases were synthesized. Their structures, based on the binding center of cystatins, contain an azaglycine residue (Agly) in place of the evolutionarily conserved glycine residue in the N-terminal part of the enzyme binding region of cystatins. Incorporation of Agly should lead to deactivation of the acyl-enzyme complex formed against nucleophilic attack by water molecules in the final step of peptide bond hydrolysis. The majority of synthesized azapeptides shows high inhibitory potency toward the investigated cysteine proteases, papain, cathepsin B, and cathepsin K. One of them, Z-Arg-Leu-Val-Agly-Ile-Val-OMe (compound 17), which contains in its sequence the amino acid residues from the N-terminal binding segment as well as the hydrophobic residues from the first binding loop of human cystatin C, proved to be a highly potent and selective inhibitor of cathepsin B. It inhibits cathepsin B with a K-i value of 0.088 nM. To investigate the influence of the structure of compound 17 for its inhibitory properties, we determined its conformation by means of NMR studies and theoretical calculations. The Z-Arg-Leu-Val-Agly fragment, covalently linked to Cys29 of cathepsin B, was also developed and modeled, in the catalytic pocket of the enzyme, through a molecular dynamics approach, to analyze ligand-protein interactions in detail. Analysis of the simulation trajectories generated using the AMBER force field provided us with atomic-level understanding of the conformational variability of this inhibitor, which is discussed in the context of other experimental and theoretical data. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/329143
- author
- Wieczerzak, Ewa
LU
; Drabik, P
; Lankiewicz, L
; Oldziej, S
; Grzonka, Z
; Abrahamson, Magnus
LU
; Grubb, Anders
LU
and Bromme, D
- organization
- publishing date
- 2002
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Medicinal Chemistry
- volume
- 45
- issue
- 19
- pages
- 4202 - 4211
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- wos:000177913500011
- pmid:12213061
- scopus:0037068629
- ISSN
- 1520-4804
- DOI
- 10.1021/jm020850k
- language
- English
- LU publication?
- yes
- id
- 896a32fe-7ecd-4b5a-99e2-ad194aa2a50e (old id 329143)
- date added to LUP
- 2016-04-01 11:37:50
- date last changed
- 2023-01-02 20:59:48
@article{896a32fe-7ecd-4b5a-99e2-ad194aa2a50e,
abstract = {{A series of azapeptides as potential inhibitors of cysteine proteases were synthesized. Their structures, based on the binding center of cystatins, contain an azaglycine residue (Agly) in place of the evolutionarily conserved glycine residue in the N-terminal part of the enzyme binding region of cystatins. Incorporation of Agly should lead to deactivation of the acyl-enzyme complex formed against nucleophilic attack by water molecules in the final step of peptide bond hydrolysis. The majority of synthesized azapeptides shows high inhibitory potency toward the investigated cysteine proteases, papain, cathepsin B, and cathepsin K. One of them, Z-Arg-Leu-Val-Agly-Ile-Val-OMe (compound 17), which contains in its sequence the amino acid residues from the N-terminal binding segment as well as the hydrophobic residues from the first binding loop of human cystatin C, proved to be a highly potent and selective inhibitor of cathepsin B. It inhibits cathepsin B with a K-i value of 0.088 nM. To investigate the influence of the structure of compound 17 for its inhibitory properties, we determined its conformation by means of NMR studies and theoretical calculations. The Z-Arg-Leu-Val-Agly fragment, covalently linked to Cys29 of cathepsin B, was also developed and modeled, in the catalytic pocket of the enzyme, through a molecular dynamics approach, to analyze ligand-protein interactions in detail. Analysis of the simulation trajectories generated using the AMBER force field provided us with atomic-level understanding of the conformational variability of this inhibitor, which is discussed in the context of other experimental and theoretical data.}},
author = {{Wieczerzak, Ewa and Drabik, P and Lankiewicz, L and Oldziej, S and Grzonka, Z and Abrahamson, Magnus and Grubb, Anders and Bromme, D}},
issn = {{1520-4804}},
language = {{eng}},
number = {{19}},
pages = {{4202--4211}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of Medicinal Chemistry}},
title = {{Azapeptides structurally based upon inhibitory sites of cystatins as potent and selective inhibitors of cysteine proteases}},
url = {{http://dx.doi.org/10.1021/jm020850k}},
doi = {{10.1021/jm020850k}},
volume = {{45}},
year = {{2002}},
}