Compound/Combination Selection Core

作者：Richard C. 复合/组合选择核心(核心E) A.对核心的描述。表1.测试代理摘要 慢性阻塞性肺疾病和慢性阻塞性肺疾病的发病机制是多因素的，但 类代理名称 包括一个常见的致病步骤：粘液纤毛的减少 粘液高渗盐水 净空(MCC)。基于形成TPPG基础的研究 水剂甘露醇 项目I和II，已经观察到正常的粘液清除ENaC调节器 需要对主航道表面进行充分的水化(请参阅计划 概述)。然而，慢性阻塞性肺疾病和慢性阻塞性肺疾病患者都表现出还原N-乙酰半胱氨酸的增加 鼻道粘液浓度(固体百分比)，由于减少了鼻道用药Nacystelyn DTT(和派生词) 由于CFTR功能障碍(1)、粘蛋白高分泌(2)或 厄多司坦 HWO的组合。其结果是出现了依附于艾恩韦的镀金 粘液斑块与纤毛和咳嗽依赖粘液的减慢 清除，导致慢性呼吸道感染。因此，开发阿奇霉素粘液 促进主路粘液清除的治疗方法可能表达CemprA 修改剂吉列德 使慢性阻塞性肺疾病/慢性阻塞性肺病患者受益。Core E的主要目标是支持所有 通过确定最有效的治疗表面活性剂/荧光素来实现tPPG的计划 增粘剂，增强粘液的粘附性和传输性。洗涤剂DPPC 作为这个tPPG项目的一部分，我们已经确定了一些Survanta职业 泰洛沙普 候选治疗药物，预计会改变 TweenSO 粘液，促进其清除。这些潜在的类别和示例 表1中总结了各种试剂。其他钙离子螯合剂 因为粘液的粘弹性是浓度依赖的，所以粘液裂解剂使低分子肝素 右旋糖苷 哪些会增加粘液的水合状态(称为水化器) 小苏打 研究(3)。这将包括渗透激素(如高渗盐水和透明质酸 甘露醇)以及ENaC介导的体液重吸收的改进剂， 测试代理类 包括：ENAC阻滞剂(Parion P552和PI 527)和ENaC修饰剂 粘液粘液 活动(QUB和Splunk)。作为降低粘液粘液浓度的替代方法 浓度，我们还将评估大环内酯类药物的使用，这些大环内酯类药物一直是粘液溶解物质/ 显示减少粘液表达(4)。除了阿奇霉素，我们还将测试 来自Cempra和Gilead的一系列新的大环内酯类药物 优化以提高他们的活跃度(请参阅支持函)。 除了降低粘液浓度外，我们还将寻求 确定降低其粘弹性和粘附性的试剂，方法是改变 粘蛋白-粘蛋白和粘蛋白-蛋白质的相互作用。二硫基还原剂 预计会通过降低粘液的粘弹性来降低粘弹性 粘蛋白单体头尾相连的链状结构。除了现有的减少 试剂(例如N-乙酰半胱氨酸和DTT)我们还将测试新的还原 干扰素诱导的溶酶体硫醇还原酶等药物 (Gilt)来自耶鲁大学的Peter Cresswell博士和各种新颖的重组- Parion的DTT(DTT-R)可提高效率和持续时间 操作(请参阅程序

Boucher, Richard C. Compound/Combination Selection Core (Core E) A. Description of the Core. Table 1. Summary of test agents The pathogenesis of CF and COPD lung disease is multi-factorial, but Class Agent Name includes a common disease-initiating step: the reduction of mucociliary Mucus Hypertonic saline clearance (MCC). Based on studies shaping the foundation of the tPPG Hydrators Mannitol Projects I and II, it has been observed that normal mucus clearance ENaC modulators requires adequate hydration of the ainway surface (see Program Overview). However, both CF and COPD patients exhibit an increase in Reducing N- acetylcysteine ainway mucus concentration (% solids), as a result of reduced ainway Agents Nacystelyn DTT (and derivitives) hydration, due to CFTR dysfunction (1), mucin hypersecretion (2), or a Erdosteine combination of the hwo. The result is the appearance of ainway-adherent GILT mucus plaques and the slowing of both cilial- and cough-dependent mucus clearance, leading to chronic ainway infections. Therefore, developing Mucus Azithromycin therapies to enhance the clearance of mucus from the ainways is likely to Expression Cempra Modifiers Gilead benefit patients with CF/COPD. The primary goal of Core E is to support all the Projects of the tPPG by identifying the most effective therapeutic Surfactants/ Lucinactant agents to enhance the dis-adherence and transportability of mucus. Detergents DPPC As part of this tPPG project, we have identified a number of classes of Survanta Tyloxapol candidate therapeutic agents, which are predicted to alter the properties of TweenSO mucus, facilitating its clearance. These classes and examples of potential agents are summarized in Table 1. Other Ca^* Chelators Because the viscoelasticity of mucus is concentration dependant, agents Mucolytics Low MW heparin Dextran which increase the hydration state of mucus (called hydrators) will be Bicarbonate studied (3). This will include osmolytes (such as hypertonic saline and Hyaluronic acid mannitol) as well as modifiers of ENaC-mediated fluid reabsorption, Test Agent Class including: ENaC blockers (Parion P552 and PI 527) and modifiers of ENaC Modihers of Modifiers ol Mucus Mucus activity (QUB and SPLUNK). As an alternative approach to reduce mucus Visco(?tc!5ticitv Concentration concentration, we will also evaluate the use of macrolides, which have been Mucolytics/ shown to reduce mucus expression (4). As well as Azithromycin, we will test a series of novel macrolide agents from Cempra and Gilead which are optimized to improve their activity (see Letters of Support). In addition to lowering the concentration of mucus, we will also seek to identify agents which reduce its viscoelasticity and adhesivity, by altering mucin-mucin and mucin-protein interactions. Di-sulfhydryl reducing agents are predicted to decrease the viscoelasticity of mucus by decreasing the head-to-tail chaining of mucin monomers. In addition to existing reducing agents (e.g. N-acetylcysteine and DTT) we will also test novel reducing agents such as Gamma-interferon-inducible lysosomal thiol reductase (GILT) from Dr. Peter Cresswell (Yale) and a variety of novel recombinant- DTTs (DTT-Rs) from Parion which increase the efficiency and duration of action (see Program