医学
组织纤溶酶原激活剂
溶栓
纤溶酶原激活剂
特里夫
纤维蛋白
纤溶酶
药理学
内科学
免疫学
化学
生物化学
心肌梗塞
受体
Toll样受体
先天免疫系统
酶
作者
Yanyan Xu,Dan Chen,Peiwen Liu,Yin‐Ping Hu,Shuangzhou Peng,Shanli Chen,Yongkun Li,Wei Lin,Longguang Jiang,Cai Yuan,Mingdong Huang
标识
DOI:10.1016/j.ijpharm.2023.122878
摘要
Recombinant tissue-type plasminogen activator (rtPA, or Alteplase) is the first approved thrombolytic drug for acute ischemic stroke, but suffers from a short half-life and poor resistance to plasminogen activator inhibitor (PAI-1), limiting its clinical use. The development of novel thrombolytic agents with improved benefit/risk balance has always been of great significance. In this study, we identified a mutant of serine protease domain of tPA (named ΔtPAA146V) capable of escaping the inhibition by endogenous PAI-1 with 66-fold increased resistance compared to the wild type tPA. Based on this mutant, we generated a triple fusion ΔtPA (TriF-ΔtPA) containing albumin and fibrin binding peptide(FBP). The fusion with albumin effectively prolonged the plasma half-life of ΔtPA in mice to 144 min, which is much longer than ΔtPA and did not affect its thrombolytic activity. Furthermore, FBP rendered fibrin specificity of the fusion protein, giving a dissociation constant of ∼ 25 ± 0.9 μM. In a novel murine carotid embolism-induced stroke (CES) model, i.v. administration of TriF-ΔtPA promoted vascular recanalization, reduced infarct volume, and mitigated neurobehavioral deficits more significantly compared to ΔtPA-HSA or Alteplase, showing little bleeding risk. Together, this long-acting PAI-1-resistant thrombolytic agent holds great potential for clinical applications.
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