title: 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.affiliation: Department of Ophthalmology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kigasawa
authors.forename: H
authors.initials: H
authors.lastname: Murata
authors.forename: Y
authors.initials: Y
authors.lastname: Morita
authors.forename: S
authors.initials: S
authors.lastname: Odake
authors.forename: E
authors.initials: E
authors.lastname: Suda
authors.forename: I
authors.initials: I
authors.lastname: Shimizu
authors.forename: T
authors.initials: T
authors.lastname: Morikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Nagai
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D002057:Burns, Chemical / Q000209:etiology; D003315:Cornea / Q000187:drug effects* / Q000473:pathology; D003320:Corneal Ulcer / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004355:Drug Stability; D005126:Eye Burns / Q000139:chemically induced; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009504:Neutrophils / Q000201:enzymology; D009824:Ointments; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009883:Ophthalmic Solutions; D011817:Rabbits; D012867:Skin / Q000201:enzymology; D012972:Sodium Hydroxide; D013237:Stereoisomerism
chemical_list: C095170:4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009824:Ointments; D009842:Oligopeptides; D009883:Ophthalmic Solutions; D012972:Sodium Hydroxide