Carbohydrate-based Therapy for Lung Disease

项目摘要 本申请的目的是将我们发现的粘液病理学的未知机制转化为 一种粘液溶解药物策略，可以使数百万粘液相关性肺病患者受益。 具体来说，我们发现CF中的粘液弹性是由中性粒细胞氧化应激引起的， 将粘蛋白聚合物连接到气道粘液凝胶上。因为氧化应激发生在多种情况下 与炎症和环境暴露相关，我们假设氧化应激是一种 普遍存在的和以前未被怀疑的原因增加粘液弹性的疾病。这提供 开发具有广泛临床用途的粘液溶解药物的原理，这些药物可以切割二硫键作为 作用机制。我们的tPPG小组已经合成了新的硫醇修饰的碳水化合物（“硫醇- 并显示它们在CF痰中具有有效的粘液溶解活性。我们有令人鼓舞的 其干粉配方的初步数据以及有关其安全性的可靠数据。我们现在 提出三个由两个核心支持的项目，将巯基糖作为一种新的治疗方法引入临床， CF和其他粘液相关的肺部疾病。项目1将修改碳水化合物支架来创建一个库 合成粘液溶解化合物，进行铅优化研究，并制定硫醇， 以干粉形式递送。项目2将筛选巯基-糖库的粘液溶解功效，以帮助 鉴定先导化合物和临床前候选化合物，并将鉴定 可能受益于粘液溶解治疗的哮喘患者。项目3将把铅硫醇化合物进展到 临床前候选物，然后作为囊性纤维化中粘液病理学的新型粘液溶解策略应用于临床。 核心A和B将在行政、财务、通信、 数据管理和集成以及人体受试者。我们的建议是及时的和高度临床相关的， 它有强有力的初步数据和实现我们目标的很大希望作为支持。 PHS 398/2590（Rev.06/09）

Project Summary The goal of this application is to translate our discovery of an unsuspected mechanism of mucus pathology into a mucolytic drug strategy that could benefit millions of patients with mucus-associated lung disease. Specifically, we have discovered that mucus elasticity in CF results from neutrophil oxidant stress that cross- links mucin polymers to stiffen the airway mucus gel. Because oxidative stress occurs in multiple situations associated with inflammation and environmental exposures, we hypothesize that oxidative stress is a ubiquitous and previously unsuspected cause of increases in mucus elasticity in disease. This provides rationale for developing mucolytic drugs with wide clinical utility that can cleave disulfide bonds as a mechanism of action. Our tPPG group has synthesized novel thiol-modified carbohydrate compounds (“thiol- saccharides”) and shown them to have potent mucolytic activity in CF sputum. We have encouraging preliminary data for their formulation as dry powders and reassuring data regarding their safety. We now propose three projects supported by two cores to bring a thiol-saccharide to the clinic as a new treatment for CF and other mucus-associated lung diseases. Project 1 will modify carbohydrate scaffolds to create a library of synthetic mucolytic compounds, conduct lead optimization studies, and formulate thiol-saccharides for delivery as dry powders. Project 2 will screen the mucolytic efficacy of thiol-saccharide library to aid in identification of lead compounds and the preclinical candidate compound and will identify a sub-population of asthmatics who may benefit from mucolytic treatment. Project 3 will progress the lead thiol-saccharides to a preclinical candidate and then to the clinic as a novel mucolytic strategy for mucus pathology in cystic fibrosis. Cores A and B will provide all three projects with support in areas of administration, finance, communication, data management and integration and human subjects. Our proposal is timely and highly clinically relevant, and it is supported by strong preliminary data and high promise for realizing our goal. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page