A Synthetic Factor XIIa Inhibitor Blocks Selectively Intrinsic Coagulation Initiation

详细信息    查看全文

• 作者：Vanessa Baeriswyl ; Sara Calzavarini ; Shiyu Chen ; Alessandro Zorzi ; Luca Bologna ; Anne Angelillo-Scherrer ; Christian Heinis
• 刊名：ACS Chemical Biology
• 出版年：2015
• 出版时间：August 21, 2015
• 年：2015
• 卷：10
• 期：8
• 页码：1861-1870
• 全文大小：742K
• ISSN：1554-8937

文摘

Coagulation factor XII (FXII) inhibitors are of interest for the study of the protease in the intrinsic coagulation pathway, for the suppression of contact activation in blood coagulation assays, and they have potential application in antithrombotic therapy. However, synthetic FXII inhibitors developed to date have weak binding affinity and/or poor selectivity. Herein, we developed a peptide macrocycle that inhibits activated FXII (FXIIa) with an inhibitory constant K_i of 22 nM and a selectivity of >2000-fold over other proteases. Sequence and structure analysis revealed that one of the two macrocyclic rings of the in vitro evolved peptide mimics the combining loop of corn trypsin inhibitor, a natural protein-based inhibitor of FXIIa. The synthetic inhibitor blocked intrinsic coagulation initiation without affecting extrinsic coagulation. Furthermore, the peptide macrocycle efficiently suppressed plasma coagulation triggered by contact of blood with sample tubes and allowed specific investigation of tissue factor initiated coagulation.