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Bacterial growth inhibited by a synthetic inhibitor based upon the structure of a human proteinase inhibitor

Björck, Lars LU ; Åkesson, Per LU ; Bohus, Martin; Trojnar, Jerzy; Abrahamson, Magnus LU ; Olafsson, Isleifur and Grubb, Anders LU (1989) In Nature 337(6205). p.385-386
Abstract
Cysteine proteinases are important not only in the intracellular catabolism of peptides and proteins1 and in the processing of prohormones and proenzymes2,3, but also in the penetration of normal human tissue by malignant cells4 and possibly microorganisms5, including viruses. Cystatin C is a human cysteine proteinase inhibitor present in extracellular fluids6. We have synthesized peptide derivatives mimicking the proposed proteinase-binding centre of cystatin C7 and find that they irreversibly inhibit cysteine proteinases. Several bacteria produce proteinases, so we tested a tripeptide derivative (Z-LVG-CHN2) for in vitro anti-bacterial activity against a large number of bacterial strains belonging to thirteen different species. It was... (More)
Cysteine proteinases are important not only in the intracellular catabolism of peptides and proteins1 and in the processing of prohormones and proenzymes2,3, but also in the penetration of normal human tissue by malignant cells4 and possibly microorganisms5, including viruses. Cystatin C is a human cysteine proteinase inhibitor present in extracellular fluids6. We have synthesized peptide derivatives mimicking the proposed proteinase-binding centre of cystatin C7 and find that they irreversibly inhibit cysteine proteinases. Several bacteria produce proteinases, so we tested a tripeptide derivative (Z-LVG-CHN2) for in vitro anti-bacterial activity against a large number of bacterial strains belonging to thirteen different species. It was found to inhibit specifically the growth of all strains of group A streptococci. The susceptibility of these human pathogens to the peptide was compared with that to well-established anti-streptococcal antibiotics such as tetracy-cline and bacitracin. Moreover, the peptide was active in vivo against group A streptococci: mice injected with lethal doses of these bacteria were cured by a single injection of Z-LVG-CHN2. The cysteine proteinase produced by group A streptococci was isolated and found to be inhibited by Z-LVG-CHN2; moreover, excess proteinase relieved the growth inhibition caused by the peptide derivative, suggesting that the antibacterial activity of Z-LVG-CHN2 is due to inhibition of this cysteine proteinase. This strategy of blocking proteinases with peptide derivatives that mimic naturally occurring inhibitors could be useful in the construction of new agents against other microorganisms, including viruses. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature
volume
337
issue
6205
pages
385 - 386
publisher
Nature Publishing Group
external identifiers
  • scopus:0024546648
ISSN
0028-0836
DOI
10.1038/337385a0
language
English
LU publication?
yes
id
ab6e42ed-f5cf-427f-b40e-5586557b9e2d (old id 1104872)
date added to LUP
2008-08-07 09:25:39
date last changed
2017-11-19 03:29:23
@article{ab6e42ed-f5cf-427f-b40e-5586557b9e2d,
  abstract     = {Cysteine proteinases are important not only in the intracellular catabolism of peptides and proteins1 and in the processing of prohormones and proenzymes2,3, but also in the penetration of normal human tissue by malignant cells4 and possibly microorganisms5, including viruses. Cystatin C is a human cysteine proteinase inhibitor present in extracellular fluids6. We have synthesized peptide derivatives mimicking the proposed proteinase-binding centre of cystatin C7 and find that they irreversibly inhibit cysteine proteinases. Several bacteria produce proteinases, so we tested a tripeptide derivative (Z-LVG-CHN2) for in vitro anti-bacterial activity against a large number of bacterial strains belonging to thirteen different species. It was found to inhibit specifically the growth of all strains of group A streptococci. The susceptibility of these human pathogens to the peptide was compared with that to well-established anti-streptococcal antibiotics such as tetracy-cline and bacitracin. Moreover, the peptide was active in vivo against group A streptococci: mice injected with lethal doses of these bacteria were cured by a single injection of Z-LVG-CHN2. The cysteine proteinase produced by group A streptococci was isolated and found to be inhibited by Z-LVG-CHN2; moreover, excess proteinase relieved the growth inhibition caused by the peptide derivative, suggesting that the antibacterial activity of Z-LVG-CHN2 is due to inhibition of this cysteine proteinase. This strategy of blocking proteinases with peptide derivatives that mimic naturally occurring inhibitors could be useful in the construction of new agents against other microorganisms, including viruses.},
  author       = {Björck, Lars and Åkesson, Per and Bohus, Martin and Trojnar, Jerzy and Abrahamson, Magnus and Olafsson, Isleifur and Grubb, Anders},
  issn         = {0028-0836},
  language     = {eng},
  number       = {6205},
  pages        = {385--386},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Bacterial growth inhibited by a synthetic inhibitor based upon the structure of a human proteinase inhibitor},
  url          = {http://dx.doi.org/10.1038/337385a0},
  volume       = {337},
  year         = {1989},
}