Matsueda R, Umeyama H, Puri R N, Bradford H N, Colman R W
New Lead Research Laboratories, Sanko, Tokyo.
Pept Res. 1994 Jan-Feb;7(1):32-5.
Thrombin-induced platelet aggregation has been suggested to play an important role in reocclusion following thrombolytic therapy or angioplasty for treatment of myocardial infarction. We previously demonstrated that thrombin-induced platelet aggregation is indirectly mediated by intracellularly activated calpain expressed on the platelet surface through the cleavage of aggregin, a putative ADP-receptor, and that high molecular weight kininogen (HK), a naturally occurring thiol protease inhibitor, modulates thrombin-induced platelet aggregation. Considering the substrate specificity of calpain and the conserved sequence in HK, we studied selective inhibitors of thrombin-induced platelet aggregation by the affinity labeling approach with an S-3-nitro-2-pyridinesulfenyl (Npys) group. H-Phe-Gln-Val-Val-Cys (Npys)-Gly-NH2, which combines chemical and structural features of calpain substrate specificity and the conserved sequence in HK, selectively inhibited thrombin-induced platelet aggregation. It did not inhibit the aggregatory effects of other platelet agonists, and did not inhibit amidolytic activity of thrombin and thrombin-induced platelet shape change. The design and synthesis of such inhibitors could lead to the development of a new class of inhibitors that selectively block thrombin-induced platelet aggregation.
凝血酶诱导的血小板聚集被认为在溶栓治疗或血管成形术治疗心肌梗死后的再闭塞中起重要作用。我们之前证明，凝血酶诱导的血小板聚集是由血小板表面细胞内活化的钙蛋白酶通过裂解聚集素（一种假定的ADP受体）间接介导的，并且高分子量激肽原（HK），一种天然存在的硫醇蛋白酶抑制剂，可调节凝血酶诱导的血小板聚集。考虑到钙蛋白酶的底物特异性和HK中的保守序列，我们通过用S-3-硝基-2-吡啶亚磺酰基（Npys）基团的亲和标记方法研究了凝血酶诱导的血小板聚集的选择性抑制剂。H-Phe-Gln-Val-Val-Cys（Npys）-Gly-NH2结合了钙蛋白酶底物特异性的化学和结构特征以及HK中的保守序列，选择性地抑制凝血酶诱导的血小板聚集。它不抑制其他血小板激动剂的聚集作用，也不抑制凝血酶的酰胺水解活性和凝血酶诱导的血小板形状变化。此类抑制剂的设计和合成可能会导致开发出一类新的选择性阻断凝血酶诱导的血小板聚集的抑制剂。
