增强蛋白C与血栓蛋白的相互作用会导致凝块激活的抗凝剂
M A Richardson1, B Gerlitz, B W Grinnell
1Department of Cardiovascular Research, Lilly Research Laboratories, Indianapolis, Indiana 46285-0424.
Nature
|November 19, 1992
概括
工程设计的蛋白C显示出通过血栓激活的增强,提供了一种新的抗凝固药疗法. 这种局部激活剂显示出治疗血栓性疾病的潜力,仅在需要时抑制血块形成.
科学领域:
- 生物化学 生物化学
- 血液学 血液学 血液学
- 分子生物学分子生物学
背景情况:
- 人类蛋白C是一种依赖维生素K的葡萄糖蛋白,作为一个不活跃的细胞原体.
- 活性蛋白C (APC) 具有抗凝固剂,益红蛋白溶解剂,抗缺血症和抗炎性质.
- 目前的活性蛋白C疗法由于生物半衰期短,因此面临局限性.
研究的目的:
- 为了设计一个修饰的蛋白质C zymogen,增强激活.
- 开发一种局部激活的抗凝剂,用于血栓性疾病.
- 克服现有的蛋白C疗法的局限性.
主要方法:
- 改变了靠近血栓分裂部位的两个酸性残留物,以增加α-血栓的基质利用率.
- 将这些变化与转基因糖形式结合起来.
- 产生了一种新型的蛋白C"proform",通过自由α-血栓增加了裂变速度.
主要成果:
- 通过自由的α-血栓,独立于血栓模块素,实现了60倍的 cleavage 速率.
- 工程设计的蛋白C的"proform"可以通过血栓激活在凝固人体血中.
- 在激活后,已证明抑制进一步的血栓形成.
结论:
- 成功设计了一个局部激活的蛋白C代理.
- 这种工程化蛋白C只有在产生显著的血栓激素时才表现出抗凝活性.
- 代表了对血栓性疾病治疗的有前途的进展.
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