A High-Throughput Assay-SOD1 Aggregation Inhibitors(RMI)

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）影响约35，000名美国人，可以说是成人发病的神经退行性疾病中最有害的，因为其相对较早发病，并且在诊断和死亡之间进展迅速。ALS没有有效的治疗方法，预计私营部门在实现这一目标方面不会取得进展，因为尚未出现经确认的“可药物靶点”，市场太小，不值得进行密集的研究工作来确定这些靶点。该提案概述了迈向新一类ALS疗法的第一步。SOD1的聚集可能是家族性ALS的致病因素。以前，我们已经证明，SOD的聚集耦合到二聚体SOD分解成单体。我们相信，稳定的二聚体形式的超氧化物歧化酶的小药物样分子可能是一个可行的策略，开发一个新的类ALS治疗。我们建议从100，000个药物样分子的文库中筛选（1）促进SOD中二聚体稳定性的分子（2）防止SOD聚集的分子。为了做到这一点，我们将开发基于荧光的检测方法，将探测SOD的二聚化和聚集。从筛选中鉴定的分子组将进行二次测定，其将依赖于这些化合物阻断聚集的直接能力。我们的长期目标是使用筛选和药物化学的组合来开发可以在ALS小鼠模型中测试的化合物。我们的最终目标是确定有理由申请IND状态的候选人。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS), which affects about 35,000 Americans, is arguably the most pernicious of the adult-onset neurodegenerative diseases because of its relatively early onset and rapid progression between diagnosis and death. There is no effective treatment for ALS and no progress towards this goal is expected from the private sector, since confirmed "druggable targets" have not emerged and the market is too small to justify an intense research effort to identify such targets. This proposal outlines a first step towards a new class of ALS therapeutics. Aggregation of SOD1 may be pathogenic in familial ALS. Previously, we have demonstrated that aggregation of SOD is coupled to the dissociation of dimeric SOD into monomers. We believe that stabilization of the dimeric form of SOD by small drug-like molecules may be a viable strategy to develop a new class of ALS therapeutics. We propose to screen a library of 100,000 drug-like molecules for (1) Molecules that promote dimer stability in SOD (2) Prevent aggregation of SOD. In order to do this, we will develop fluorescence-based assays that will probe both dimerization and aggregation of SOD. The set of molecules identified from the screen will be subjected to secondary assays which will rely on the direct ability of these compounds to block aggregation. Our long term goal is to use a combination of screening and medicinal chemistry to develop compounds that can be tested in a mice model for ALS. Our ultimate goal is to identify candidates that justify filing for IND status.