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。在制药工业中已经做出了广泛的努力来开发安全有效的抗血小板药物以预防和治疗这些医学病症。血栓性血管疾病新疗法开发的一个主要目标是整合素受体？二？3.现有口服可用？二？3拮抗剂，开发的目的是阻断纤维蛋白原结合其受体，有令人失望的结果。这些化合物与受体的开放活性构象相互作用，并将其保持在该形式。维护？二？3的开放构象导致基本上组成型活性血小板，这可能对这些细胞的存活有害。因此，一个潜在的原因，令人失望的结果，临床研究与口服？二？3拮抗剂可能是他们的维持持续？二？3信号传导可以抵消阻断纤维蛋白原结合的治疗作用。开发能维持？二？3的构象将阻止纤维蛋白原结合，从而阻止血栓形成，但也防止？二？3信令可能克服与可用相关的问题？二？3个拮抗剂。Encode Bio开发了一种光学技术，可用于以高通量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中发现的缺点。Encode Bio提出开发一种药物筛选测定（基于其光学技术），可用于识别整合素受体的变构抑制剂？二？3.公共卫生相关性：与血栓形成相关的死亡率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？3.识别选择性结合到这种整联蛋白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提出开发一种药物筛选试验，可用于识别整合素受体的变构抑制剂？二？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.