New Theraputics for Graft-Versus-Host Disease

移植物抗宿主病的新疗法

• 批准号: 7055781
• 负责人: KRISHNA KUMAR
• 金额: $ 38.8万
• 依托单位: CHEMOKINE PHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7055781
• 关键词: analog; computers; graft versus host disease; human; lead; ligands; model; proteins

DESCRIPTION (provided by applicant): The long term goal of this project is to discover and develop new therapeutic agents for graft-versus- host disease (GVHD) which is a major complication after allogeneic bone marrow transplantation (BMT) in patients with leukemia and other oncologic disorders. In addition, we intend to use this project as a model to develop a general structure-based approach to discover small molecular inhibitors of protein-protein interactions involved in T cell stimulatory pathways. The underlying hypothesis of our research is that the interaction between the CD4 protein and the major histocompatibility complex (MHC) class II protein is critical for T cell activation, and therefore small molecules interrupting such CD4-MHC class II interaction could be used as effective immunosuppressive agents. In a series of recent studies, we identified a CD4 surface pocket implicated in CD4-MHC class II interaction and T cell activation. Using a computer-based technique to screen (150,000 small organic compounds, we discovered a group of novel ligands of the CD4 surface pocket that could inhibit CD4 function. Among them, the most potent lead compound TJU103 was shown to specifically bind to the CD4 surface pocket, block CD4 interaction with MHC class II, and significantly inhibit T cell activation. We demonstrated that TJU103 is highly effective in vivo in murine GVHD. Furthermore, we found that TJU103 is orally active, not toxic, and highly selective for CD4- mediated immune response. These findings strongly suggested that TJU103 is a promising lead compound for the development of a new class of immunotherapeutics for GVHD in cancer patients undergoing BMT. Here we propose to apply an interdisciplinary approach combining organic synthesis, biological studies, and computer modeling to study the structure-activity relationship of TJU103 and develop analogs with higher potency and optimized pharmacological profiles for further pre-clinical studies and eventually clinical trials in humans.

描述（由申请人提供）：该项目的长期目标是发现和开发移植物抗宿主病（GVHD）的新治疗药物，移植物抗宿主病是白血病和骨髓移植患者异体骨髓移植（BMT）后的主要并发症。其他肿瘤疾病。此外，我们打算使用这个项目作为模型来开发一种基于通用结构的方法来发现 T 细胞刺激途径中蛋白质-蛋白质相互作用的小分子抑制剂。我们研究的基本假设是，CD4 蛋白和主要组织相容性复合物 (MHC) II 类蛋白之间的相互作用对于 T 细胞激活至关重要，因此中断这种 CD4-MHC II 类相互作用的小分子可以用作有效的免疫抑制药物。代理。在最近的一系列研究中，我们发现了一个与 CD4-MHC II 类相互作用和 T 细胞激活有关的 CD4 表面口袋。通过基于计算机的技术筛选150,000个小有机化合物，我们发现了一组可以抑制CD4功能的CD4表面口袋的新型配体。其中，最有效的先导化合物TJU103被证明可以与CD4表面特异性结合阻断 CD4 与 MHC II 类相互作用，并显着抑制 T 细胞活化。我们证明 TJU103 在体内对小鼠 GVHD 非常有效。具有口服活性，无毒，并且对 CD4 介导的免疫反应具有高度选择性。这些发现强烈表明，TJU103 是一种有前途的先导化合物，可用于开发接受 BMT 的癌症患者的 GVHD 免疫治疗药物。采用有机合成、生物学研究和计算机建模相结合的跨学科方法来研究 TJU103 的结构-活性关系，并开发具有更高效力和优化药理学特征的类似物，用于进一步的临床前研究和最终临床人体试验。