Inhibition of corneal ulceration by tetrapeptidyl hydroxamic acid.

Abstract

The inhibitory activity of a new peptidyl collagenase inhibitor, FN-439 or tetrapeptidyl hydroxamic acid (H2N-C6H4-CO-Gly-L-Pro-D-Leu-D-Ala-NHOH), was determined against vertebrate collagenases derived from human fibroblast, human polymorphonuclear leukocyte (PMN) and tadpole skin. In addition, the effect of FN-439 in inhibiting corneal ulceration was also investigated with alkali-burned rabbit corneas. FN-439 can block the active site of collagenase, and hydroxamic acid can chelate Zn2+ which is essential for collagenase activity. Furthermore, this compound contains D-amino acids to resist nonspecific host-derived degradative enzymes. In our experiments, corneal ulceration occurred in 5 of the 9 control eyes, but in none of the 9 eyes treated with FN-439 (P < 0.01). The only cellular elements observed at the ulcerated area were PMNs and monocytes. FN-439 appeared to act against PMN collagenase. In addition, we compared the change in the concentration of FN-439 (D-peptide) and the L-form of FN-439 (L-peptide) in aqueous humor aspirated from the rabbit eyes burned with alkali. After incubation for 3 hours, the concentration of the D-peptide was decreased by 3%, while that of the L-peptide was decreased by 60%. FN-439 may be useful for treating noninfectious corneal ulcers because of its potent activity (IC50 = 1 microM) and chemical and biological stabilities.

• Authors: K Kigasawa, H Murata, Y Morita, S Odake, E Suda, I Shimizu, T Morikawa, Y Nagai
• Journal: Japanese journal of ophthalmology (Jpn J Ophthalmol) Vol. 39 Issue 1 Pg. 35-42 ( 1995) ISSN: 0021-5155 [Print] Japan
• PMID: 7643481 (Publication Type: Journal Article)

Chemical References

• 4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid
• Hydroxamic Acids
• Matrix Metalloproteinase Inhibitors
• Ointments
• Oligopeptides
• Ophthalmic Solutions
• Sodium Hydroxide

Topics

• Animals
• Aqueous Humor (metabolism)
• Burns, Chemical (etiology)
• Cornea (drug effects, pathology)
• Corneal Ulcer (etiology, pathology, prevention & control)
• Drug Stability
• Eye Burns (chemically induced)
• Fibroblasts (enzymology)
• Humans
• Hydroxamic Acids (chemistry, pharmacokinetics, pharmacology)
• Male
• Matrix Metalloproteinase Inhibitors
• Neutrophils (enzymology)
• Ointments
• Oligopeptides (chemistry, pharmacokinetics, pharmacology)
• Ophthalmic Solutions
• Rabbits
• Skin (enzymology)
• Sodium Hydroxide
• Stereoisomerism