Discovery of Chemical Probes and Therapeutic Leads: Cryoprobe Upgrade of a 400 MHz NMR

项目摘要 该生物医学研究卓越中心的目标是继续努力开发分子生物学。 探索生物学的方法，发现和应用新的化学生物学工具来研究生物学， 与疾病相关的途径，并开发计算方法来了解小 分子与复杂大分子靶点的相互作用。在合成，生物化学， 我们的科学团队将开发新的化学生物学工具， 细菌病原体用于在宿主细胞内生存和复制的细胞和分子机制， 化学工具和核苷酸类似物，以了解mRNA去甲基化的调节， 擦除酶及其在人类癌症中的失调，分子定义的纳米颗粒佐剂， 肺中的特异性免疫反应，以推进可吸入疫苗的开发， 阐明小分子调节病毒结构和功能的机制的方法 衣壳 COBRE资金将用于招聘两名新的教师，他们将补充现有的优势， 我们的中心，这将通过竞争性试点赠款扩大。在眼镜蛇的第4年和第5年，5个2- 年更换项目将得到资助。在特拉华州和全国范围内开展协作和资源共享 IDEA网络对于最大限度地提高我们的研究能力、核心设施和指导网络至关重要。在 第二阶段，该COBRE继续开发独特的核心设施，促进高通量合成， 化学探针的纯化、筛选和分析。在第一阶段建立的基础设施的基础上， 我们将支持分析化学的核心设施，这将为以下关键核心设施提供支持： 质谱、溶液NMR和动力学分析。该中心还将支持一个综合和发现 核心设施，这将提供定制的合成服务和仪器和基础设施，为小 分子合成，高通量催化剂发现，并行合成，计算和显微镜。

Project Summary The goal of this Center of Biomedical Research Excellence is to continue our efforts to develop molecular approaches for probing biology, to discover and apply new chemical biology tools for the study of biological pathways associated with disease, and to develop computational approaches for understanding small molecule interactions with complex macromolecular targets. With core strengths in synthesis, biochemistry, engineering and biology, our scientific team will develop new chemical biology tools for understanding the cellular and molecular mechanisms that bacterial pathogens use to survive and replicate inside host cells, new chemical tools and nucleotide analogs to understand the regulation of mRNA demethylation by a ‘methyl eraser’ enzyme and its dysregulation in human cancer, molecularly-defined nanoparticle adjuvants that yield specific immune responses in the lung to advance inhalable vaccine development, and computational approaches to elucidate the mechanisms by which small molecules regulate the structure and function of virus capsids. COBRE funding will be used to recruit two new faculty members who will complement the existing strengths of our center, which will be expanded through competitive pilot grants. In years 4 and 5 of the COBRE, five two- year replacement projects will be funded. Collaboration and resource sharing in the Delaware and national IDeA network will be critical for maximizing our research capacity, core facilities and mentoring network. In Phase II, this COBRE continue to develop unique core facilities that facilitates high throughput synthesis, purification, screening and analysis of chemical probes. Building on the infrastructure established in Phase I, we will support a core facility in Analytical Chemistry, which will provide support for critical core facilities in mass spectrometry, solution NMR and kinetic analysis. The center will also support a Synthesis and Discovery core facility, which will provide custom synthesis services and instrumentation and infrastructure for small molecule synthesis, high throughput catalyst discovery, parallel synthesis, computation and microscopy.