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.