Allosteric Inhibitors of Coagulation Proteases

 描述(申请人提供)：本项目试图开发新的分子作为凝血酶，特别是凝血酶和凝血因子XIA的变构抗凝剂。假说是通过对其催化三联体的变构破坏来靶向这些酶 导致受控抑制，很可能不会出现出血后果。所有目前的抗凝剂，包括肝素、华法林、达比卡特兰和利伐沙班，都存在出血风险增加的问题。在过去的授权期内，产生了两组非常有希望的凝血酶和XIA因子抑制剂。凝血酶抑制剂具有调节功能(最大抑制率为50-75%)，很可能维持止血，特别是在预防性应用的情况下。同样，凝血因子XIA抑制剂很可能没有出血。 这是因为Xia因子的内在作用机制，即它在作用于血栓形成过程的同时，保持止血过程不变。此外，变构抑制剂被预测具有更高的作用特异性，这将减少脱靶效应。因此，预计这两组抑制剂将导致更安全的抗凝治疗。事实上，我们已经发现，我们设计的一个分子在FeCl3诱导的颈动脉小鼠模型血栓形成中显示出显著的抗凝血活性，而不影响出血时间，支持这一假说。在此授权期内，我们打算：i)设计更有效、更具选择性的人类凝血酶调节剂；ii)开发更有效、更具选择性的人类凝血因子Xia抑制剂；以及iii)对前景看好的先进凝血酶调节剂和FXIa抑制剂进行临床前研究。

 DESCRIPTION (provided by applicant): This project attempts to develop novel molecules as allosteric anticoagulants of coagulation proteases, especially thrombin and factor XIa. The hypothesis is that targeting these proteases through allosteric disruption of their catalytic triad results in controlled inhibition, which is likely to not suffer from bleeding consequences. All current anticoagulants including the heparins, warfarin, dabigatran and rivaroxaban suffer from enhanced risk of bleeding. The past grant period resulted in two groups of highly promising inhibitors of thrombin and factor XIa. The thrombin inhibitors displayed regulatory features (maximal inhibition in the region of 50 - 75%), which is likely to maintain hemostasis, especially under prophylactic application. Likewise, factor XIa inhibitors are likely to be devoid of bleeding because of the inherent mechanism of action of factor XIa, which is its action on the thrombotic process while leaving hemostatic process intact. In addition, the allosteric inhibitors are predicted to possess a higher specificity of action, which would reduce off target effects. Thus, the two groups of inhibitors are predicted to lead to a safer anticoagulant therapy. In fact, we have found that one of our designed molecules showed marked anticoagulant activities in FeCl3-induced thrombosis in the carotid artery mouse model without affecting bleeding time supporting the hypothesis. In this grant period, we intend to I) design more potent, selective regulators of human thrombin; II) develop more potent, selective inhibitors of human factor XIa and III) perform pre-clinical studies on promising advanced thrombin regulators and FXIa inhibitors.