Design & Synthesis of Novel Agents to Treat Amyloidosis

描述(由申请人提供)：我们建议的项目的主要目标是促进用于治疗淀粉样变性和其他蛋白质聚集性疾病的新化合物的开发。初步工作表明，两种查尔酮在体外抑制淀粉样原纤维的形成，进一步的工作是有必要的。由非免疫球蛋白引起的淀粉样蛋白疾病包括成人起病的糖尿病(II型糖尿病)、阿尔茨海默病、唐氏综合征、全身性家族性淀粉样变性、老年性淀粉样变性和β2-微球蛋白(透析相关)淀粉样变性。到目前为止，还没有开发出有效的治疗药物来防止这些疾病中的蛋白质聚集。治疗蛋白质聚集性疾病的药物存在着相当大的商业市场。据估计，全球有1000万人患有阿尔茨海默氏症，总人口的6%被诊断为II型糖尿病，发达国家每年有千分之一的人死于淀粉样变性。在我们为治疗蛋白质聚集引起的蛋白质紊乱而发现小分子的持续研究中，我们开发了一种经济、方便的高通量方法，用于在微孔板中筛选抗原纤维形成的化合物，并在体外试验中鉴定出许多查尔酮分子是淀粉样原纤维形成的抑制剂。在我们的第一阶段研究计划中，将在分子建模分析的基础上设计新的查尔酮，使用平行合成方法合成并使用LEN VL蛋白筛选对淀粉样纤维形成的抑制活性。此外，将在分子模拟分析的基础上，产生LEN VL蛋白的突变体，用于鉴定和确认查尔酮结合位点。从这一第一阶段计划中获得的成功结果将成为我们SBIR第二阶段研究的基础。预计，在我们的第二阶段计划结束时，不仅可以为IND指导的全面临床前研究选择理想的候选者，导致在SBIR第二阶段计划中提交IND并启动临床试验，而且可能更重要的是，所获得的知识和开发的技术将适用于并扩展到其他蛋白质聚集性疾病。

DESCRIPTION (provided by applicant): The major goal of our proposed project is to advance the development of novel compounds for the treatment of amyloidosis and other protein aggregation diseases. Preliminary work demonstrated that two chalcones inhibited amyloid fibril formation, in vitro, and that further work is warranted. The amyloid diseases that arise from nonimmunoglobulin proteins include adult onset diabetes (type II diabetes), Alzheimer's disease, Down's syndrome, systemic familial amyloidosis, senile amyloid disease and beta 2-microglobulin (dialysis associated) amyloidosis. Effective therapeutic agents that prevent protein aggregation in these diseases have not been developed to date. A commercial market of significant size exists for drugs that treat protein aggregation diseases. It is estimated that 10 million people worldwide suffer from Alzheimer's disease, 6% of the total population have been diagnosed with type II diabetes and that 1/1000 people in developed countries die annually from amyloidosis. In our continuing research efforts to discover small molecules for the treatment of protein disorders caused by protein aggregation, we developed an economical and convenient high-throughput method for screening compounds against fibril formation in microwell plates and identified a number of chalcone molecules as inhibitors of amyloid fibril formation in the in vitro assay. During our Phase I research program, novel chalcones will be designed, based on the molecular modeling analysis, synthesized using a parallel synthesis approach and screened for the inhibitory activity against amyloid fibril formation using LEN VL protein. Furthermore, mutants of the LEN VL protein will be generated for the identification and confirmation of chalcone binding sites, based on molecular modeling analysis. The successful results obtained from this Phase I program will be the foundation of our SBIR Phase II studies. It is anticipated that, at the conclusion of our Phase II program, not only can an ideal candidate be selected for full IND-directed preclincial studies leading to an IND submission and initiation of clinical trials in the SBIR Phase Ill program, but also and, perhaps more importantly, the knowledge gained and technology developed will be applicable and be extended to other protein aggregation diseases.