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Cystatin C based peptidyl diazomethanes as cysteine proteinase inhibitors: Influence of the peptidyl chain length

Hall, Anders; Abrahamson, Magnus LU ; Grubb, Anders LU ; Trojnar, Jerzy; Kania, Piotr; Kasprzykowska, Regina and Kasprzykowski, Franciszek (1992) In Journal of Enzyme Inhibition and Medicinal Chemistry 6(2). p.113-123
Abstract
The peptidyl diazomethanes Cbz-Gly-CHN2, Boc-Val-Gly-CHN2, H-Leu-Val-Gly-CHN2, Cbz-Leu-Val-Gly-CHN2 and Cbz-Arg-Leu-Val-Gly-CHN2, with peptidyl portions modelled after the proposed cysteine proteinase interacting N-terminal segment of human cystatin C, were synthesized. Their efficiency as cysteine proteinase inhibitors was tested against papain, human cathepsin B and bovine cathepsin B. All, except Cbz-Gly-CHN2, were found to be irreversible inhibitors of the tested enzymes. Each addition of an amino acid residue to their peptidyl portions resulted in an increased inhibition rate of all three enzymes. These data suggest that the arginyl residue of the tetrapeptidyl diazomethane, and also the corresponding arginyl residue in native... (More)
The peptidyl diazomethanes Cbz-Gly-CHN2, Boc-Val-Gly-CHN2, H-Leu-Val-Gly-CHN2, Cbz-Leu-Val-Gly-CHN2 and Cbz-Arg-Leu-Val-Gly-CHN2, with peptidyl portions modelled after the proposed cysteine proteinase interacting N-terminal segment of human cystatin C, were synthesized. Their efficiency as cysteine proteinase inhibitors was tested against papain, human cathepsin B and bovine cathepsin B. All, except Cbz-Gly-CHN2, were found to be irreversible inhibitors of the tested enzymes. Each addition of an amino acid residue to their peptidyl portions resulted in an increased inhibition rate of all three enzymes. These data suggest that the arginyl residue of the tetrapeptidyl diazomethane, and also the corresponding arginyl residue in native cystatin C, interact with a S4 substrate pocket subsite of both papain and cathepsin B. The most efficient inhibitor, Cbz-Arg-Leu-Val-Gly-CHN2, inhibited papain and cathepsin B with rate constants of the same order of magnitude as those for L-3-carboxy-trans-2.3-epoxypropionyl-leucylamido-(4-guanidino)butane (E-64). The high water-solubility of Cbz-Arg-Leu-Val-Gly-CHN2 allowing it to be dissolved to molar concentrations without use of non-physiological additives, makes it suitable for in vitro and in vivo cysteine proteinase inhibition studies. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cathepsin B, papain, Keywords: Cystatin C, peptidyl diazomethanes, irreversible inhibitors
in
Journal of Enzyme Inhibition and Medicinal Chemistry
volume
6
issue
2
pages
113 - 123
publisher
Informa Healthcare
external identifiers
  • scopus:0026671365
ISSN
1475-6374
DOI
10.3109/14756369209040742
language
English
LU publication?
yes
id
79ddc73a-7c33-4793-85f2-2ad2c281ab9e (old id 1106864)
date added to LUP
2008-08-01 15:54:06
date last changed
2017-11-19 03:29:28
@article{79ddc73a-7c33-4793-85f2-2ad2c281ab9e,
  abstract     = {The peptidyl diazomethanes Cbz-Gly-CHN2, Boc-Val-Gly-CHN2, H-Leu-Val-Gly-CHN2, Cbz-Leu-Val-Gly-CHN2 and Cbz-Arg-Leu-Val-Gly-CHN2, with peptidyl portions modelled after the proposed cysteine proteinase interacting N-terminal segment of human cystatin C, were synthesized. Their efficiency as cysteine proteinase inhibitors was tested against papain, human cathepsin B and bovine cathepsin B. All, except Cbz-Gly-CHN2, were found to be irreversible inhibitors of the tested enzymes. Each addition of an amino acid residue to their peptidyl portions resulted in an increased inhibition rate of all three enzymes. These data suggest that the arginyl residue of the tetrapeptidyl diazomethane, and also the corresponding arginyl residue in native cystatin C, interact with a S4 substrate pocket subsite of both papain and cathepsin B. The most efficient inhibitor, Cbz-Arg-Leu-Val-Gly-CHN2, inhibited papain and cathepsin B with rate constants of the same order of magnitude as those for L-3-carboxy-trans-2.3-epoxypropionyl-leucylamido-(4-guanidino)butane (E-64). The high water-solubility of Cbz-Arg-Leu-Val-Gly-CHN2 allowing it to be dissolved to molar concentrations without use of non-physiological additives, makes it suitable for in vitro and in vivo cysteine proteinase inhibition studies.},
  author       = {Hall, Anders and Abrahamson, Magnus and Grubb, Anders and Trojnar, Jerzy and Kania, Piotr and Kasprzykowska, Regina and Kasprzykowski, Franciszek},
  issn         = {1475-6374},
  keyword      = {cathepsin B,papain,Keywords: Cystatin C,peptidyl diazomethanes,irreversible inhibitors},
  language     = {eng},
  number       = {2},
  pages        = {113--123},
  publisher    = {Informa Healthcare},
  series       = {Journal of Enzyme Inhibition and Medicinal Chemistry},
  title        = {Cystatin C based peptidyl diazomethanes as cysteine proteinase inhibitors: Influence of the peptidyl chain length},
  url          = {http://dx.doi.org/10.3109/14756369209040742},
  volume       = {6},
  year         = {1992},
}