CORE--SYNTHETIC /MEDICINAL CHEMISTRY

合成/药物化学核心（SynCore）将为CF计划项目的新型小分子疗法提供至关重要的技术。该计划的总体目标是发现新型CF相关小分子，其用作突变CFTR的增强剂、校正剂deltaF 508-CFTR细胞错误处理、CFTR抑制剂、非病毒基因递送的增强剂、用于鼻PD与来自CF受试者的氯转运培养细胞之间的相关性的资源、抗微生物剂、基于水通道蛋白的腺液分泌增强剂、增强肺泡液清除的CFTR激活剂，腺粘蛋白分泌的抑制剂，长期抑制猪CFTR功能的资源，用于确定ASL在CF先天免疫防御中的作用的试剂，用于确定缺陷型CFTR的作用的试剂， CF肺病中的气道粘膜下腺体分泌，以及用于高通量筛选的命中-先导发现文库。SynCore将在该计划中发挥重要作用，通过准备旨在探索高通量筛选提供的命中的先导化合物发现库，并提供项目2中概述的研究所需的研究相关量的先导化合物，来实现这些目标。SynCore的具体目标是：（1）制备化学纯的、结构表征的小分子HIT和LEAD化合物，供项目和核心应用;（2）制备命中-先导发现文库，旨在从结构上探索通过高通量筛选鉴定的命中。

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.