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）：本项目的长期目标是发现和开发新的治疗药物，用于治疗移植物抗宿主病（GVHD），GVHD是白血病和其他肿瘤疾病患者异基因骨髓移植（BMT）后的主要并发症。此外，我们打算使用这个项目作为一个模型，开发一个通用的基于结构的方法，发现小分子抑制剂的蛋白质-蛋白质相互作用参与T细胞刺激途径。我们的研究的基本假设是，CD 4蛋白和主要组织相容性复合体（MHC）II类蛋白之间的相互作用是T细胞活化的关键，因此，小分子干扰这种CD 4-MHC II类相互作用可以用作有效的免疫抑制剂。在最近的一系列研究中，我们确定了一个CD 4表面口袋涉及CD 4-MHC II类相互作用和T细胞活化。利用计算机技术筛选了15万种小分子有机化合物，我们发现了一组新的CD 4表面口袋配体，它们可以抑制CD 4功能。其中，最有效的先导化合物TJU 103显示出特异性结合CD 4表面口袋，阻断CD 4与MHC II类相互作用，并显著抑制T细胞活化。我们证明了TJU 103在小鼠GVHD中体内是高度有效的。此外，我们发现TJU 103具有口服活性，无毒，并且对CD 4介导的免疫应答具有高度选择性。这些发现有力地表明，TJU 103是一种有前途的先导化合物，用于开发一类新的免疫治疗药物，用于接受BMT的癌症患者的GVHD。在这里，我们建议采用有机合成，生物学研究和计算机建模相结合的跨学科方法来研究TJU 103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的人体临床试验。