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

项目摘要 可用于治疗囊性纤维化(CF)等呼吸道疾病中的病理性粘液的治疗药物， 哮喘和COPD在数量、疗效和耐受性方面都是有限的。因为过多的粘蛋白 在CF中，二硫键使呼吸道粘液凝胶变硬，我们合成了硫醇修饰的糖(“硫醇-糖”)。 糖“)作为一种新的药物类别，裂解二硫键具有良好的粘液溶解活性。这个 选择碳水化合物支架的理由是它们是极性的、廉价的、“天然的”、通常是结晶的， 由于其丰富的羟基和手性中心，提供了容易获得类似物的结构 活度关系(SAR)研究。初步数据显示，我们文库中精选的硫代糖具有 与N-乙酰半胱氨酸等硫醇氨基酸化合物相比，起效更快，效力更强。我们的 初步数据也为体外硫醇糖(呼吸道上皮细胞)的安全性提供了保证 和活体内(小鼠肺)。因此，我们提出了两个目标来推进硫醇的药物开发计划- 糖作为一种新的粘液溶解疗法治疗囊性纤维化和其他相关粘液的粘液病理 肺部疾病。在目标1中，我们将设计和合成一个硫醇糖库来研究和建立 SARS的粘液溶解作用(与项目2合作)以及它们的毒性和其他 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 硫代糖的物理化学性质、雾化特性和喷雾干燥稳定性 以优化配方为目标的无赋形剂/最小赋形剂、高活性负载的化合物 具有合适的物理化学和空气动力学特性的微粒，可用于肺部干燥给药 粉末吸入器。AIM 2还将与其他活性药物成分共同形成硫醇糖类 如β激动剂、抗胆碱能药、皮质类固醇和重组人脱氧核糖核酸酶。

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.