Design & Synthesis of Novel Agents to Treat Amyloidosis

描述（由申请人提供）：我们提出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疾病的新型化合物的开发。初步工作表明，两个查耳酮抑制淀粉样纤维的形成，在体外，并保证进一步的工作。由非免疫球蛋白引起的淀粉样疾病包括成人发病糖尿病（II型糖尿病）、阿尔茨海默病、唐氏综合征、系统性家族性淀粉样变性、老年淀粉样疾病和β 2-微球蛋白（透析相关）淀粉样变性。迄今为止，尚未开发出防止这些疾病中蛋白质聚集的有效治疗剂。对于治疗蛋白质聚集疾病的药物而言，存在相当大规模的商业市场。据估计，全世界有1000万人患有阿尔茨海默病，总人口的6%已被诊断患有II型糖尿病，并且发达国家每年有1/1000的人死于淀粉样变性。在我们持续的研究努力，以发现小分子的蛋白质聚集引起的蛋白质疾病的治疗，我们开发了一种经济和方便的高通量的方法，用于筛选化合物对原纤维形成的微孔板，并确定了一些查耳酮分子作为抑制剂的淀粉样蛋白原纤维形成的体外试验。在我们的I期研究计划中，将基于分子建模分析设计新型查耳酮，使用平行合成方法合成，并使用LEN VL蛋白筛选对淀粉样蛋白原纤维形成的抑制活性。此外，LEN VL蛋白的突变体将产生的查耳酮结合位点的鉴定和确认，基于分子建模分析。从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II期项目结束时，不仅可以选择理想的候选人进行全面的IND指导的临床前研究，从而提交IND并启动SBIR III期项目的临床试验，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.