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

高通量检测-SOD1聚集抑制剂(RMI)

• 批准号: 7022025
• 负责人: PETER T LANSBURY
• 金额: $ 21.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022025
• 关键词: amyotrophic lateral sclerosis; biotechnology; chemical aggregate; combinatorial chemistry; drug discovery /isolation; drug screening /evaluation; enzyme inhibitors; high throughput technology; inhibitor /antagonist; neuropharmacologic agent; small molecule; superoxide dismutase; technology /technique development

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.

描述（由申请人提供）：肌萎缩侧索硬化症 (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致命的，因为其发病相对较早，并且在诊断和死亡之间进展迅速。 ALS 没有有效的治疗方法，并且预计私营部门在实现这一目标方面不会取得进展，因为尚未出现确认的“药物靶标”，而且市场太小，无法证明需要进行大量研究工作来确定此类靶标。该提案概述了迈向新型 ALS 疗法的第一步。 SOD1 的聚集可能在家族性 ALS 中具有致病性。之前，我们已经证明 SOD 的聚集与二聚体 SOD 解离成单体有关。我们相信，通过类药小分子稳定二聚体形式的 SOD 可能是开发新型 ALS 疗法的可行策略。我们建议筛选 100,000 个类药分子库，以寻找 (1) 促进 SOD 二聚体稳定性的分子 (2) 防止 SOD 聚集。为了做到这一点，我们将开发基于荧光的检测方法来探测 SOD 的二聚化和聚集。从筛选中鉴定出的一组分子将进行二次测定，这将依赖于这些化合物阻止聚集的直接能力。我们的长期目标是结合筛选和药物化学来开发可在 ALS 小鼠模型中进行测试的化合物。我们的最终目标是找到有理由申请 IND 状态的候选人。