Kigasawa K, Murata H, Morita Y, Odake S, Suda E, Shimizu I, Morikawa T, Nagai Y
Department of Ophthalmology, Tokai University School of Medicine, Isehara, Japan.
Jpn J Ophthalmol. 1995;39(1):35-42.
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.
一种新型肽基胶原酶抑制剂FN - 439或四肽基异羟肟酸（H2N - C6H4 - CO - Gly - L - Pro - D - Leu - D - Ala - NHOH）对源自人成纤维细胞、人多形核白细胞（PMN）和蝌蚪皮肤的脊椎动物胶原酶的抑制活性进行了测定。此外，还利用碱烧伤的兔角膜研究了FN - 439在抑制角膜溃疡方面的作用。FN - 439可阻断胶原酶的活性位点，而异羟肟酸可螯合对胶原酶活性至关重要的Zn2+。此外，该化合物含有D - 氨基酸以抵抗非特异性宿主来源的降解酶。在我们的实验中，9只对照眼中有5只发生了角膜溃疡，但9只接受FN - 439治疗的眼中均未发生（P < 0.01）。在溃疡区域观察到的唯一细胞成分是PMN和单核细胞。FN - 439似乎对PMN胶原酶起作用。此外，我们比较了从碱烧伤的兔眼中抽取的房水中FN - 439（D - 肽）和FN - 439的L型（L - 肽）浓度的变化。孵育3小时后，D - 肽的浓度降低了3%，而L - 肽的浓度降低了60%。由于其强大的活性（IC50 = 1 microM）以及化学和生物学稳定性，FN - 439可能对治疗非感染性角膜溃疡有用。
