New Theraputics for Graft-Versus-Host Disease

项目描述（由申请人提供）：该项目的长期目标是发现和开发新的治疗移植物抗宿主病（GVHD）的药物，GVHD是白血病和其他肿瘤疾病患者同种异体骨髓移植（BMT）后的主要并发症。此外，我们打算利用这个项目作为一个模型，开发一种基于一般结构的方法，以发现参与T细胞刺激途径的蛋白质-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体（MHC） II类蛋白之间的相互作用对T细胞活化至关重要，因此阻断CD4-MHC II类相互作用的小分子可以用作有效的免疫抑制剂。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细胞活化有关的CD4表面口袋。使用基于计算机的技术筛选（150,000个小有机化合物），我们发现了一组新的CD4表面口袋配体，可以抑制CD4功能。其中，最有效的先导化合物TJU103被证明可以特异性结合CD4表面口袋，阻断CD4与MHC II类的相互作用，并显著抑制T细胞活化。我们证明了TJU103在体内对小鼠GVHD非常有效。此外，我们发现TJU103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是一种有希望的先导化合物，可用于开发一类新的免疫疗法，用于治疗接受BMT的癌症患者的GVHD。在此，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TJU103的结构-活性关系，并开发具有更高效力和优化药理特征的类似物，用于进一步的临床前研究和最终的人体临床试验。

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.