后他汀，一种脯氨酰内肽酶的新型抑制剂。V. 后他汀类似物的内肽酶抑制活性。

Poststatin, a new inhibitor of prolyl endopeptidase. V. Endopeptidase inhibitory activity of poststatin analogues.

作者信息

Tsuda M, Muraoka Y, Nagai M, Aoyagi T, Takeuchi T

机构信息

Institute of Microbial Chemistry, Tokyo, Japan.

出版信息

J Antibiot (Tokyo). 1996 Sep;49(9):890-9. doi: 10.7164/antibiotics.49.890.

DOI:10.7164/antibiotics.49.890

PMID:8931723

Abstract

Thirty analogues of poststatin were synthesized, and their inhibitory activities against prolyl endopeptidase, human leukocyte elastase and cathepsin B were measured. The alpha-ketone was essential and the S configuration was preferable to the R configuration in the beta-substituted-beta-amino-alpha-oxopropionic acid moiety of poststatin analogues for endopeptidase inhibitory activity. The analogue in which the D-leucine residue of poststatin was replaced by L-leucine showed strong inhibitory activity to cathepsin B. Introduction of an aromatic group into the P4 position and proline into the P2 position increased inhibitory activity to elastase. Benzyloxycarbonyl-L-homophenylalanyl-(RS)- 3-amino-2-oxovaleryl-D-leucyl-L-valine was about 6 times more active to prolyl endopeptidase than natural poststatin.

摘要

合成了30种poststatin类似物，并测定了它们对脯氨酰内肽酶、人白细胞弹性蛋白酶和组织蛋白酶B的抑制活性。α-酮是必需的，在poststatin类似物的β-取代-β-氨基-α-氧代丙酸部分中，S构型比R构型更有利于内肽酶抑制活性。将poststatin的D-亮氨酸残基替换为L-亮氨酸的类似物对组织蛋白酶B表现出较强的抑制活性。在P4位引入芳基和在P2位引入脯氨酸可增强对弹性蛋白酶的抑制活性。苄氧羰基-L-高苯丙氨酰-(RS)-3-氨基-2-氧代戊酰-D-亮氨酰-L-缬氨酸对脯氨酰内肽酶的活性约为天然poststatin的6倍。