CORE--SYNTHETIC /MEDICINAL CHEMISTRY

合成/药物化学核心(SynCore)将提供对这一用于CF的新型小分子疗法计划项目至关重要的使能技术。这个计划的总体目标是发现新的与cf相关的小分子，它们可以作为突变cftr的增强剂、校正deltaF508-cftr细胞错误处理的纠正器、cftr抑制剂、非病毒基因传递的增强剂、鼻部pd和来自cf受试者的氯离子转运培养细胞之间的关联资源、抗菌剂、以水通道蛋白为基础的腺液分泌增强剂、增强肺泡液清除的cftr激活剂、腺粘蛋白分泌的抑制剂、长期抑制cftr功能的资源、有助于确定asl在cf天然免疫防御中的作用的试剂、有助于确定有缺陷的cf的作用的试剂。 慢性阻塞性肺疾病患者的呼吸道粘膜下腺分泌物，以及高通量筛选的Hit-to-Lead发现文库。SynCore将通过准备先导发现库，探索高通量筛选提供的HITS，并提供PROJECTs2中概述的研究所需的与研究相关的数量，在实现这些目标的努力中发挥重要作用。SynCore的具体目标是(1)制备化学上纯净的、具有结构特征的小分子Hit和Lead化合物，供项目和核心应用，以及(2)准备Hit-to-Lead发现库，旨在从结构上探索通过高通量筛选确定的Hit。

The Synthesis/Medicinal Chemistry Core (SynCore) will provide enabling technology vital to this NOVEL SMALL-MOLECULE THERAPIES FOR CF program project. The overall goal of this program is the discovery of novel CF-relevant small-molecules which serve as potentiators of mutant CFTRs, correctors deltaF508-CFTR cellular misprocessing, CFTR inhibitors, enhancers of non-viral gene delivery, resources for correlation between nasal PDs and chloride transport cultured cells from CF subjects, antimicrobials, aquaporin-based enhancers of gland fluid secretion, CFTR activators to enhance alveolar fluid clearance, inhibitors of glandular mucin secretion, resources to chronically inhibit CFTR function in pigs, reagents useful in defining the role of ASL in innate immune defense in CF, reagents useful in defining the role of defective airway submucosal gland secretion in CF lung disease, and hit-to-lead discovery libraries for high-throughput screening. SynCore will figure prominently in this program's efforts to realize these objectives by preparing lead discovery libraries designed to explore hits provide by high-throughput screening and providing study-relevant quantities of the lead compounds required for the studies outlined in the PROJECTs2. The SynCore specific aims are to (1) prepare chemically pure, structurally characterized small-molecule HIT and LEAD compounds for application by the PROJECTS and the COREs and (2) prepare hit-to-lead discovery libraries designed to structurally explore hits identified by high-throughput screening.