NOVEL DRUG DISCOVERY FOR RHEUMATOID ARTHRITIS

类风湿关节炎新药的发现

• 批准号: 6989817
• 负责人: Peter R Rhode
• 金额: $ 11.22万
• 依托单位: ALTOR BIOSCIENCE. LLC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-13 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989817
• 关键词: MHC class II antigen; T cell receptor; T lymphocyte; affinity chromatography; autoimmunity; cytotoxicity; drug discovery /isolation; enzyme linked immunosorbent assay; high throughput technology; immunosuppression; immunotherapy; intermolecular interaction; leukocyte activation /transformation; muscle disorder chemotherapy; protein protein interaction; rheumatoid arthritis; small molecule

DESCRIPTION (provided by applicant): The long-term objective of this project is to develop small molecule inhibitors of MHC class II activity for the treatment of rheumatoid arthritis (RA). The strong genetic association between specific MHC class II alleles, such as HLA-DR molecules containing the shared epitope, and susceptibility to RA provides support to a mechanism in which disease-associated MHC molecules selectively activate CD4 T cells. The hypothesis of this project is that small molecules that block T cell receptor (TCR):HLA-DR-peptide complex formation can prevent autoreactive T cell activation and chronic inflammatory processes in the affect joints. The investigator has developed sensitive screening assays to detect TCR:HLA-DR-peptide interactions and methods to produce sufficient amounts of soluble and functional TCR and HLA-DR-peptide reagents to support analysis of libraries of small molecules. Preliminary studies with another TCR:HLA-peptide pair demonstrate that compounds that specifically inhibit HLA activity in vitro and in vivo can be identified using these screening methods. The specific aims of the project are to further develop high-throughput screening assays to identify and characterize small molecules that inhibit TCR:HLA-DR-peptide interactions, to examine a large and diverse collection of small molecules for inhibitory activity and to test the immunosuppressive effects of these compounds in T cell-based assays. The results from these studies will provide useful information about TCR:HLA-peptide interactions and could form the basis of a novel class of immunosuppressive drugs to treat human T-cell mediated autoimmune diseases.

描述（由申请人提供）：该项目的长期目标是开发用于治疗类风湿关节炎（RA）的MHC II类活性的小分子抑制剂。特定的MHC II类等位基因之间的强遗传关联，例如包含共享表位的HLA-DR分子，RA易感性为与疾病相关的MHC分子选择性激活CD4 T细胞的机制提供了支持。该项目的假设是，堵塞T细胞受体（TCR）的小分子：HLA-DR肽复合物的形成可以防止感应关节中自动反应性T细胞活化和慢性炎症过程。研究者已经开发了敏感的筛选测定方法来检测TCR：HLA-DR肽相互作用和方法，以产生足够量的可溶性和功能性TCR和HLA-DR肽试剂，以支持对小分子文库的分析。使用另一种TCR：HLA肽对的初步研究表明，可以使用这些筛选方法在体外和体内特异性抑制HLA活性的化合物。该项目的具体目的是进一步开发高通量筛选测定法，以识别和表征抑制TCR：HLA-DR肽相互作用的小分子，以检查抑制活性的大量小分子集合并测试免疫抑制作用这些化合物在基于T细胞的测定中的作用。这些研究的结果将提供有关TCR：HLA肽相互作用的有用信息，并可能构成一类新型免疫抑制药物的基础，以治疗人类T细胞介导的自身免疫性疾病。