水蛭素及水蛭素PA相关抗凝肽中硫酸化的位置效应

Positional effects of sulfation in hirudin and hirudin PA related anticoagulant peptides.

作者信息

Payne M H, Krstenansky J L, Yates M T, Mao S J

机构信息

Merrel Dow Research Institute, Cincinnati, Ohio 45215.

出版信息

J Med Chem. 1991 Mar;34(3):1184-7. doi: 10.1021/jm00107a043.

DOI:10.1021/jm00107a043

PMID:2002458

Abstract

C-Terminal fragment analogues of the leech protein hirudin or the related protein hirudin PA block thrombin's cleavage of fibrinogen. Three series of synthetic peptides were synthesized to study the effects of sulfation in hirudin-derived peptides. Potency of hirudin analogues increased with p-(amino)Phe63, p-(aminosulfonate)Phe63, and p-(sulfate)Tyr63 substitution in place of Tyr63. Sulfation of Tyr56, which in hirudin is normally Phe, resulted in a loss of 1 order of magnitude in potency. The sulfation of Tyr64 of the hirudin PA related analogue resulted in increased potency as for the hirudin analogue. However, in this series the p-(amino)Phe64 and p-(amino-sulfonate)Phe64 did not have increased potency. In addition to these positional effects, replacing all the Glu residues with (O-sulfato)Ser yielded an analogue with full antithrombin potency.

摘要

水蛭蛋白水蛭素或相关蛋白水蛭素PA的C末端片段类似物可阻断凝血酶对纤维蛋白原的裂解。合成了三个系列的合成肽，以研究水蛭素衍生肽中硫酸化的作用。水蛭素类似物的效力随着用对（氨基）苯丙氨酸63、对（氨基磺酸盐）苯丙氨酸63和对（硫酸盐）酪氨酸63取代酪氨酸63而增加。在水蛭素中通常为苯丙氨酸的酪氨酸56的硫酸化导致效力损失1个数量级。水蛭素PA相关类似物的酪氨酸64的硫酸化导致效力增加，与水蛭素类似物相同。然而，在这个系列中，对（氨基）苯丙氨酸64和对（氨基磺酸盐）苯丙氨酸64并没有增加效力。除了这些位置效应外，用（O-硫酸化）丝氨酸取代所有谷氨酸残基产生了一种具有完全抗凝血酶效力的类似物。