Discovery of Chemical Probes and Therapeutic Leads, Phase 2

项目总结 父母科布尔奖的目标是发现化学探针和治疗线索， 是开发探索生物学的化学方法，发现和应用新的化学生物工具 研究与疾病相关的生物途径，并了解小分子之间的相互作用 分子及其生物靶标使用计算方法。在这份补充奖申请中， 我们建议开发探针和抑制剂，并使用这些新工具来研究基础生化 ADAM9是一种细胞表面金属蛋白酶，是一种生物标志物和潜在的治疗靶点 多种人类疾病。该应用程序的目标1(由魏博士领导)将专注于开发敏感和 ADAM9的选择性荧光肽底物，目前还无法获得。这些多肽底物 是高通量筛选以识别ADAM9抑制剂以及产生生物传感器以 检测动物和临床样本中内源性ADAM9的活性作为生物标志物。目标2(由施密茨博士领导) 我们将使用一种ADAM9抑制剂来研究ADAM9与抑制剂相互作用的分子基础 最近确认的。这些信息对于指导未来识别和优化ADAM9至关重要 抑制剂。在目标3(由朗汉斯博士领导)中，我们将通过以下方法测试识别新的ADAM9抑制剂的可行性 用包含数千种化合物的文库进行中等吞吐量的筛选。确定的命中率 这一筛选将作为进一步优化开发有效和选择性的ADAM9抑制剂的线索 研究和临床用途。拟议的研究将利用以下独特和互补的技能集 每位合作项目负责人：魏博士是一位经验丰富的研究人员，专门从事金属蛋白酶生物化学 和细胞生物学，施密茨博士是一名结构生物学家，专注于蛋白酶结构-功能关系，以及 内穆尔儿童医院高通量屏幕核心设施的代理主任朗汉斯博士说， 将贡献她在药物筛选方面的专业知识。协作将是高度协同的、广泛的 预计三个研究小组之间的互动将针对每个目标。在这个项目完成时， 我们希望使用这项研究产生的数据提交一份多PI R01申请，以继续和 深化合作。总之，拟议的合作研究将具有长期和 对了解相关疾病的病理和开发新药的变革性影响 治疗这些疾病。

PROJECT SUMMARY The goal of the parental COBRE award, entitled Discovery of Chemical Probes and Therapeutic Leads, is to develop chemical approaches for probing biology, to discover and apply new chemical biological tools for the study of disease-associated biological pathways, and to understand the interactions between small molecules and their biological targets using computational approaches. In this supplement award application, we propose to develop probes and inhibitors and use these new tools to study the fundamental biochemical properties of ADAM9, a cell-surface metalloproteinase that is a biomarker and a potential therapeutic target for multiple human diseases. Aim 1 of this application (led by Dr. Wei) will be focused on developing sensitive and selective fluorescent peptide substrates for ADAM9, which are currently unavailable. These peptide substrates are necessary for high-throughput screens to identify ADAM9 inhibitors, and for generating biosensors to detect endogenous ADAM9 activity in animal and clinical samples as a biomarker. Aim 2 (led by Dr. Schmitz) will investigate the molecular basis of ADAM9-inhibitor interactions by using an ADAM9 inhibitor that we recently identified. This information is crucial for guiding future identification and optimization of ADAM9 inhibitors. In Aim 3 (led by Dr. Langhans), we will test the feasibility of identifying new ADAM9 inhibitors by conducting a medium-throughput screen with a library containing thousands of compounds. Hits identified in this screen will serve as leads for further optimization to develop potent and selective ADAM9 inhibitors for research and clinical purposes. The proposed study will leverage the unique and complementary skill set of each co-project leader: Dr. Wei is an experienced researcher specializing in metalloproteinase biochemistry and cell biology, Dr. Schmitz is a structural biologist focusing on protease structure-function relationship, and Dr. Langhans, the acting director of the High-Throughput Screen Core Facility at Nemours Children’s Hospital, will contribute her expertise in drug screen. The collaboration will be highly synergistic, as extensive interactions among the three research groups are anticipated for each aim. At the completion of this project, we expect to submit a multi-PI R01 application using the data generated from this study to continue and deepen our collaboration. In conclusion, the proposed collaborative research will have a long-term and transformative impact on understanding the pathology of the related diseases and developing new drugs to treat these diseases.