Modified Carbohydrate Scaffolds for the Treatment of Mucus Disease of the Airway

项目摘要 用于治疗气道疾病如囊性纤维化（CF）中的病理性粘液的可用治疗剂， 哮喘和COPD在数量、功效和耐受性方面受到限制。因为过多的粘蛋白 二硫键在CF中覆盖气道粘液凝胶，我们合成了巯基修饰的二硫键（“巯基- ”）作为一类新的药物，其切割二硫键以具有优异的粘液溶解活性。的 选择碳水化合物支架的基本原理是它们是极性的、便宜的、“天然的”，通常是结晶的，并且， 由于其丰富的羟基基团以及手性中心， 活性关系（SAR）研究。初步数据显示，在我们的文库中选择的巯基-β-内酰胺具有 比巯基氨基酸化合物如N-乙酰半胱氨酸起效更快，效力更好。我们 初步数据还提供了体外（气道上皮细胞）硫醇的安全性保证 和体内（小鼠肺）。因此，我们提出了两个目标，以推进硫醇的药物开发计划- 作为囊性纤维化和其他粘液相关疾病中粘液病理的新型粘液溶解治疗 肺部疾病在目标1中，我们将设计和合成一个巯基-β-内酰胺文库，以研究和建立 SAR的粘液溶解作用（与项目2合作）及其毒性和其他 药代动力学特性（与项目3合作）。在目标2中，我们将评估合成的 硫代巴比妥的物理化学性质、气溶胶化特性和喷雾干燥稳定性 化合物的目标是优化配方，作为无赋形剂/赋形剂最小化，高活性负载 具有合适的物理化学和空气动力学性质的微粒， 粉末吸入器。AIM 2还将与其他活性药物成分共同配制硫醇 例如β激动剂、抗胆碱能药、皮质类固醇和rhDNA酶。

Project Summary Available therapeutics for treatment of pathologic mucus in airway diseases such as cystic fibrosis (CF), asthma, and COPD are limited in number, efficacy, and tolerability. Because excessive numbers of mucin disulfide bonds stiffen the airway mucus gel in CF, we have synthesized thiol-modified saccharides (“thiol- saccharides”) as a novel drug class that cleaves disulfide bridges to have excellent mucolytic activity. The rationale behind choosing a carbohydrate scaffold is that they are polar, cheap, “natural”, often crystalline, and, with their abundance of hydroxyl groups as well as chiral centers, offer easy access to analogues for structure activity relationship (SAR) studies. Preliminary data show that selected thiol-saccharides in our library have a faster onset of action and better potency than thiol amino acid compounds such as N-acetyl cysteine. Our preliminary data also provide reassurance about the safety of thiol-saccharides in vitro (airway epithelial cells) and in vivo (mouse lungs). We therefore propose two Aims to advance a drug development program for thiol- saccharides as a novel mucolytic treatment for mucus pathology in cystic fibrosis and other mucus associated lung diseases. In Aim 1 we will design and synthesize a library of thiol-saccharides to investigate and establish SARs for their mucolytic effect (in collaboration with Project 2) as well as their toxicity and other pharmacokinetic properties (in collaboration with Project 3). In Aim 2 we will evaluate the synthetic thiolsaccharides for their physicochemical properties, aerosolization characteristics, and stability as spray dried compounds with the goal to optimize formulation as excipient-free/excipient-minimized, high active loaded microparticles with suitable physicochemical and aerodynamic properties for pulmonary delivery via dry powder inhaler. Aim 2 will also co-formulate thiol-saccharides with other active pharmaceutical ingredients such as beta agonists, anticholinergics, corticosteroids, and rhDNAse.