Novel assay to identify anti-thrombotic agents

描述（由申请人提供）：血小板过度聚集导致血栓形成和血管闭塞，导致许多心血管疾病，包括心肌梗死和中风。为了预防和治疗这些疾病，制药行业已经做出了广泛的努力，开发安全有效的抗血小板药物。整合素受体是开发血栓性血管疾病新疗法的一个主要靶点。二世?3. 现有的或可用的？二世?以阻断纤维蛋白原与其受体结合为目标开发的3种拮抗剂的结果令人失望。这些化合物与受体开放的、活跃的构象相互作用，并使其保持这种形式。维护吗?二世?开放构象中的3导致本质上构成活跃的血小板，这可能对这些细胞的存活有害。因此，临床研究结果令人失望的一个潜在原因是口服？二世?3 .拮抗剂可能是它们的维持持续？二世?3信号传导可以抵消阻断纤维蛋白原结合的治疗作用。开发变构抑制剂可以维持？二世?失活构象会阻止纤维蛋白原结合，从而阻断血栓形成。二世?3 .信号可能克服与可用性相关的问题？二世?3拮抗剂。Encode Bio开发了一种光学技术，该技术可以以高通量的方式测量蛋白质从非活性状态到活性状态的构象变化，而没有其他生物物理技术的缺点。Encode Bio提议开发一种药物筛选试验（基于其光学技术），可用于识别整合素受体的变构抑制剂。二世?3. 公共卫生相关性：与血栓形成相关的死亡率的增加导致了许多药物的开发，以减少血小板聚集，用于治疗血栓性血管疾病。最近抗血栓药物开发的一个主要焦点是整合素受体的抑制剂。二世?3. 识别选择性结合这种整合素受体的非活性构象的变构抑制剂可以产生比目前可用的更有效的拮抗剂。为了发现变构抑制剂，人们需要有一种方法来测量受体的非活性构象并检测其向活性形式的转变。Encode Bio提议开发一种药物筛选试验，可用于鉴定整合素受体的变构抑制剂。二世?3.

DESCRIPTION (provided by applicant): Excessive platelet aggregation leading to thrombosis and vascular occlusion causes a number of cardiovascular disorders including myocardial infarction and stroke. Extensive efforts have been made in the pharmaceutical industry to develop safe and effective anti-platelet drugs to prevent and treat these medical conditions. A major target in the development of new treatments of thrombotic vascular disorders is the integrin receptor ?II? 3. Existing orally-available ?II? 3 antagonists, developed with a goal of blocking the binding of fibrinogen to its receptor, have had disappointing results. These compounds interact with the open, active conformation of the receptor and maintain it in that form. Maintaining ?II? 3 in an open conformation results in essentially a constitutively active platelet, which may be detrimental to the survival of these cells. Therefore, one potential reason for the disappointing results of clinical studies with oral ?II? 3 antagonists may be that their maintenance of continued ?II? 3 signaling could counter the therapeutic effects of blocking fibrinogen binding. Developing allosteric inhibitors that could maintain ?II? 3 in an inactivate conformation would prevent fibrinogen binding, thereby blocking thrombosis but also prevent ?II? 3 signaling possibly overcoming the problems associated with available ?II? 3 antagonists. Encode Bio has developed an optical technology which can be employed to measure conformational changes in proteins from inactive to active states in a high throughput manner without the drawbacks found in other biophysical techniques. Encode Bio proposes to develop a drug screening assay (based on its optical technology) which can be employed to identify allosteric inhibitors of the integrin receptor ?II? 3. PUBLIC HEALTH RELEVANCE: The increasing mortality associated with thrombosis has led to the development of a number of drugs to reduce platelet aggregation for treatment of thrombotic vascular disease. A major focus of recent anti- thrombosis drug development has been inhibitors of the integrin receptor ?II? 3. Identifying allosteric inhibitors that selectively bind to the inactive conformation of this integrin receptor could yield more effective antagonists than presently available. To discover allosteric inhibitors, one would need to have a way to measure the inactive conformation of the receptor and detect its shift to an active form. Encode Bio proposes to develop a drug screening assay which can be employed to identify allosteric inhibitors of the integrin receptor ?II? 3.