Development of inhibitors for systemic amyloid diseases

描述（由申请人提供）：由于缺乏关于疾病因子聚集的结构和原因的信息，系统性淀粉样蛋白疾病的治疗一直受到阻碍。这些物质是由具有聚集倾向的蛋白质形成的拉长的、未分枝的淀粉样纤维。纤维在器官中积累，最终衰竭。相比之下，对癌症、传染病和代谢性疾病的攻击越来越成功，部分原因在于可以获得有关疾病目标结构的信息，从而能够设计有效的化学干预措施。在以前的工作中，我们已经开发了一种抑制淀粉样蛋白纤维形成的程序。第一步是应用我们的计算机算法来识别驱动淀粉样纤维形成的类似魔术扣的短序列片段。我们已经应用该算法在疾病相关蛋白中发现了100多个这样的片段，并验证了这些片段本身形成淀粉样纤维，以及密切相关的微晶体。第二步是这些微晶的x射线结构测定，揭示了纤维形成的原子基础。第三步是利用得到的原子结构作为设计抑制剂的平台来阻止纤维的形成。整个过程是简单的，可以产生引起轻链（AL）和转甲状腺素（TTR）系统性淀粉样变性的纤维抑制剂。在我们的研究中，我们将验证免疫球蛋白轻链和转甲状腺素的特定片段是聚集的原因，并根据它们的原子结构设计聚集抑制剂。这些抑制剂将在体外和动物模型中测试其阻止纤维形成的能力。原则上，同样的方法可以用于开发其他系统性淀粉样蛋白疾病的抑制剂。

DESCRIPTION (provided by applicant): Treatments for systemic amyloid diseases have been held back by lack of information on the structures and causes of aggregation of the disease agents. These agents are the elongated, unbranched amyloid fibers formed by proteins having propensity for aggregation. The fibers accumulate in organs which eventually fail. In contrast, the increasingly successful attack on cancer, infectious, and metabolic diseases is rooted in part in the availability of information on the structures of the disease targets, permitting design of effective chemical interventions. In previous work we have developed a procedure for inhibiting the formation of amyloid fibers. This first step is application of our computer algorithm which identifies the short Velcro-like sequence segments that drive formation of amyloid fibers. We have applied this algorithm to find over 100 such segments in disease- related proteins, and have verified that such segments themselves form amyloid fibers, and closely related microcrystals. The second step is X-ray structure determination of these microcrystals, which reveal the atomic basis of fiber formation. The third step is to use the resulting atomic structure as a platform for the design of inhibitors to stop fiber formation. This overall procedure is robus and ready to produce inhibitors of fibers found that cause light-chain (AL) and transthyretin (TTR) systemic amyloidosis. In our research, we will validate particular segments of immunoglobulin light chains and transthyretin as the causes of aggregation, and based on their atomic structures, design inhibitors of aggregation. These inhibitors will be tested for their abilty to halt fiber formation in vitro, and in animal models. In principle, the same methods can be used to develop inhibitors for other systemic amyloid diseases.