Development of inhibitors for systemic amyloid diseases

描述(由申请人提供)：由于缺乏关于病原体聚集的结构和原因的信息，系统性淀粉样病的治疗一直受到阻碍。这些药物是由具有聚集倾向的蛋白质形成的细长的、未分枝的淀粉样纤维。这些纤维聚集在器官中，最终会失效。相比之下，对癌症、传染病和代谢性疾病的日益成功的攻击，部分源于关于疾病靶标结构的信息的可用性，从而允许设计有效的化学干预措施。在之前的工作中，我们开发了一种抑制淀粉样纤维形成的方法。这第一步是应用我们的计算机算法，该算法识别驱动淀粉样纤维形成的短尼龙搭扣状序列片段。我们已经应用这个算法在疾病相关蛋白中找到了100多个这样的片段，并验证了这些片段本身形成了淀粉样纤维和密切相关的微晶体。第二步是对这些微晶进行X射线结构测定，揭示纤维形成的原子基础。第三步是利用得到的原子结构作为平台，设计抑制纤维形成的抑制剂。这一整个过程是Robus和准备生产的纤维抑制剂被发现，导致轻链(AL)和转甲状腺激素(TTR)系统性淀粉样变性。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的抑制剂。这些抑制剂将在体外和动物模型中测试它们阻止纤维形成的能力。原则上，同样的方法也可以用来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.