Biological evaluation of the inhibition of neutrophil elastase by a synthetic beta-lactam derivative.
A novel beta-lactam derivative, N-(2-chloromethylphenyl) 3,3-difluoroazetidin-2-one, which behaves as a time-dependent inactivator of leukocyte elastase, has been tested in biological models designed to detect its potential therapeutic value in the treatment of emphysema. Its effect on two types of leukocyte elastase, purified human leukocyte elastase and elastase freshly discharged upon stimulation of guinea pig polymorphonuclear neutrophils, was examined using three methods: the cleavage of a chromogenic peptide substrate, MeO-Suc-Ala-Ala-Pro-Val-NA, the lysis and solubilization of tritiated elastin and the microscopic examination of the damage to lung elastic network. The inhibitor was shown to be effective at preventing proteolysis due to leukocyte elastase. Besides its low cellular toxicity, no apparent hindrance of its efficiency was found in the above quasi in vivo environment. This suggests that this inhibitor may be of potential therapeutic value in elastase-related pathology.
Maillard
J L
JL
Laboratoire de Bioactivation des Peptides, Institut Jacques Monod, Paris, France.
Favreau
C
C
Reboud-Ravaux
M
M
Kobaiter
R
R
Joyeau
R
R
Wakselman
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001384:Azetidines / Q000737:chemistry / Q000494:pharmacology; D002863:Chromogenic Compounds; D004549:Elastin / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009504:Neutrophils / Q000201:enzymology*; D009842:Oligopeptides; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000097:blood*; D012995:Solubility; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D001384:Azetidines; D002863:Chromogenic Compounds; D009842:Oligopeptides; D047090:beta-Lactams; C067251:N-(2-chloromethylphenyl)-3,3-difluoroazetidin-2-one; C067253:N-methoxysuccinyl-alanyl-alanyl-prolyl-valine-4-nitroanilide; D004549:Elastin; D010196:Pancreatic Elastase