Allosteric Inhibitors of Coagulation Proteases

凝固蛋白酶的变构抑制剂

基本信息

批准号：
9310378
负责人：
Umesh Ramanlal Desai
金额：
$ 51.08万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9310378
关键词：
Adult Affect Anticoagulant therapy Anticoagulants Anticoagulation Antidotes Antithrombin III Benzofurans Binding Binding Sites Bioavailable Biological Availability Bleeding time procedure Carotid Arteries Coagulation Process Dimerization Disease Drug Delivery Systems Drug Design Drug Interactions Drug Kinetics Electrostatics Elements Equilibrium Factor XIa Fibrinolytic Agents Functional disorder Generations Glycosaminoglycans Goals Grant Hemorrhage Hemostatic Agents Hemostatic function Heparin Heparitin Sulfate Human In Vitro Individual Investigational Drugs Lead Legal patent Libraries Mammals Modeling Morbidity - disease rate Oral Paper Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Physicians Primates Process Property Regulation Research Research Personnel Risk Safety Specificity Surgeon System Tail Therapeutic Thrombin Thromboplastin Thrombosis Time Toxic effect Triad Acrylic Resin Unspecified or Sulfate Ion Sulfates Venous Warfarin Work X-Ray Crystallography analog base carboxylate clinically relevant design dimer high throughput screening in vivo inhibitor/antagonist innovation lead sulfate mimetics mortality mouse model novel pre-clinical preclinical study programs prophylactic public health relevance scaffold structural biology

项目摘要

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.

描述（由申请人提供）：该项目试图开发新的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。假设是通过变构破坏这些蛋白酶的催化三联体来靶向这些蛋白酶。导致受控抑制，可能不会遭受出血后果，包括肝素、华法林、达比加群和利伐沙班在内的所有现有抗凝剂都会增加出血风险。过去的资助期产生了两组非常有前途的凝血酶和因子抑制剂。 XIa.凝血酶抑制剂显示出调节特征（最大抑制在50-75%范围内），这可能维持止血，特别是在预防性应用下。同样，XIa 因子抑制剂可能不会导致出血由于因子 XIa 的固有作用机制是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。预计这两组抑制剂将带来更安全的抗凝治疗。事实上，我们发现我们设计的一种分子在颈动脉小鼠模型中显示出明显的抗凝活性，而不会影响 FeCl3 血栓诱导的形成。在此资助期间，我们打算 I) 设计更有效的、选择性的人类凝血酶调节剂；II) 开发更有效的、选择性的人类因子 XIa 和 III) 对有前景的先进凝血酶进行临床前研究。调节剂和 FXIa 抑制剂。