Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA, 70125, USA.
Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA, 70125, USA.
Eur J Med Chem. 2020 Aug 15;200:112442. doi: 10.1016/j.ejmech.2020.112442. Epub 2020 May 18.
Human factor XIIIa (FXIIIa) is a multifunctional transglutaminase with a significant role in hemostasis. FXIIIa catalyzes the last step in the coagulation process. It stabilizes the blood clot by cross-linking the α- and γ-chains of fibrin. It also protects the newly formed clot from plasmin-mediated fibrinolysis, primarily by cross-linking α-antiplasmin to fibrin. Furthermore, FXIIIa is a major determinant of clot size and clot's red blood cells content. Therefore, inhibitors targeting FXIIIa have been considered to develop a new generation of anticoagulants to prevent and/or treat venous thromboembolism. Several inhibitors of FXIIIa have been discovered or designed including active site and allosteric site small molecule inhibitors as well as natural and modified polypeptides. This work reviews the structural, biochemical, and pharmacological aspects of FXIIIa inhibitors so as to advance their molecular design to become more clinically relevant.
人凝血因子 XIIIa（FXIIIa）是一种多功能转谷氨酰胺酶，在止血中具有重要作用。FXIIIa 催化凝血过程的最后一步。它通过交联纤维蛋白的 α-和 γ-链稳定血凝块。它还通过将 α-抗纤溶酶交联到纤维蛋白上来保护新形成的血栓免受纤溶酶介导的纤维蛋白溶解，主要是通过交联 α-抗纤溶酶到纤维蛋白上来保护新形成的血栓。此外，FXIIIa 是血凝块大小和血凝块中红细胞含量的主要决定因素。因此，靶向 FXIIIa 的抑制剂已被认为是开发新一代抗凝剂以预防和/或治疗静脉血栓栓塞症的候选药物。已经发现或设计了几种 FXIIIa 抑制剂，包括活性位点和变构位点小分子抑制剂以及天然和修饰的多肽。这项工作综述了 FXIIIa 抑制剂的结构、生化和药理学方面，以推进其分子设计，使其更具有临床相关性。
