Allosteric Inhibitors of Coagulation Proteases

 描述（由申请人提供）：本项目试图开发新型分子作为凝血蛋白酶的变构抗凝剂，特别是凝血酶和因子XIa。该假说是，通过变构破坏这些蛋白酶的催化三联体， 导致受控的抑制，其可能不会遭受出血后果。所有目前的抗凝剂，包括肝素、华法林、达比加群和利伐沙班，都存在出血风险增加的问题。过去的资助期导致了两组非常有前途的凝血酶和因子XIa抑制剂。凝血酶抑制剂显示出调节特征（在50 - 75%的区域中的最大抑制），这可能维持止血，尤其是在预防性应用下。同样，因子XIa抑制剂可能不会出血 这是因为因子XIa的内在作用机制，即其对血栓形成过程的作用，同时保持止血过程完整。此外，预计变构抑制剂具有更高的作用特异性，这将减少脱靶效应。因此，这两组抑制剂预计将导致更安全的抗凝治疗。事实上，我们已经发现，我们设计的分子之一显示出显着的抗凝活性，在FeCl 3诱导的血栓形成的颈动脉小鼠模型，而不影响出血时间支持的假设。在此资助期内，我们打算I）设计更有效的、选择性的人凝血酶调节剂; II）开发更有效的、选择性的人凝血因子XIa抑制剂; III）对有前景的晚期凝血酶调节剂和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.