文献：

Recombinant and chemo-/bio-orthogonal synthesis of liposomal thrombomodulin and its antithrombotic activity

文献链接：

https://pubmed.ncbi.nlm.nih.gov/28694021/

作者：

Lin Wang , Rui Jiang, Yang Liu , Maosheng Cheng, Qingyu Wu , Xue-Long Sun

相关产品：

磷脂-聚乙二醇2000-二苯基环辛炔 DSPE-PEG2000-DBCO

原文摘要：

Thrombomodulin (TM) is an endothelial cell membrane protein that acts as a major cofactor in the protein C anticoagulant pathway. The EGF-like domains 4-6 of TM (TM456) are essential for PC activation. In this study, we proposed a liposomal recombinant TM conjugate to mimic the membrane TM structure and its anticoagulant activity. First, a DSPE-PEG2000-TM456 was successfully synthesized by site-specific conjugation of azido-TM456 with DSPE-PEG2000-DBCO via copper-free click chemistry quantitatively. Then, liposome-TM456 was fabricated via direct liposome formation with the DSPE-PEG2000-TM456 and other lipids. This liposomal formulation of TM456 retained protein C activation activity as that of TM456. Also, liposome-TM456 was much more stable and had a longer plasma half-life than TM456 and DSPE-PEG2000-TM456, respectively. Moreover, liposome-TM456 showed in vivo anticoagulant effect by decreasing the mortality from 80% to 20% in a thrombin-induced thromboembolism mouse model. The reported liposome-TM456 conjugate mimics the endothelial TM anticoagulation activity and may serve as an effective anticoagulant agent candidate for future development.

图为：磷脂-聚乙二醇2000-二苯基环辛炔 DSPE-PEG2000-DBCO结构式

TM 是一种分布于内皮细胞膜表面的跨膜糖蛋白，在体内的平衡调节中有作用。在蛋白 C（Protein C，PC）抗凝途径中充当着主要的辅助因子。当凝血酶与 TM 结合后，凝血酶的活性会转变，从原本的促凝状态转变为激活蛋白 C 的关键酶。在 TM 的辅助下，凝血酶能够高效地将无活性的蛋白 C 裂解为具有抗凝活性的活化蛋白 C（Activated Protein C，APC）。

首先，通过无铜点击化学，叠氮-TM456与DSPE-PEG2000-DBCO位点特异性偶联，成功合成了DSPE-PEG 2000-TM456。然后，通过用DSPE-PEG2000-TM456和其他脂质体直接形成脂质体来制备脂质体-TM456。TM456的这种脂质体制剂保留了与TM456相同的蛋白C活化活性。

脂质体作为一种人工合成的双分子层囊泡结构，具有与细胞膜相似的物理化学性质，能够包裹和递送生物活性分子，为模拟膜蛋白的结构和功能提供平台。脂质体-TM456比TM456和DSPE-PEG2000-TM456更稳定，半衰期更长。脂质体-TM456缀合物模拟内皮TM抗凝活性，可作为候选抗凝剂。