Pathologic mucus is a major problem in asthma exacerbations, contributing significantly to mechanisms of airflow obstruction, and playing a major role in death from asthma. Despite this important role for mucus in asthma exacerbations, the mechanism underlying the formation of rubbery occlusive mucus in asthma have been poorly understood, and mucolytic therapies are limited in number, efficacy, and tolerability. Recently, the Fahy lab has shown that excessive numbers of mucin disulfide bonds represent a therapeutic target in pathologic mucus gels. In addition, the lab has shown that disulfide bonds can be broken with reducing agents such as N-acetyl cysteine (NAC). Because of the significant limitations of NAC as a therapeutic, we have collaborated with the Oscarson lab at University College Dublin to explore the utility of reducing agents using thiol-modified saccharides (thiol-saccharides). 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 high mucolytic efficacy for a candidate thiol-saccharides with multiple advantages over NAC, including faster onset of action and better potency. We propose three Aims to advance understanding of mucus pathology in acute severe asthma and to hasten a new drug development program for thiol-saccharides as a novel mucolytic treatment for mucus pathology in acute asthma.
Aim 1 will explore the role of oxidative stress as a mechanism of mucus pathology in acute severe asthma.
Aim 2 will synthesize a library of thiol-saccharides and evaluate their physicochemical properties, aerosolization characteristics, and stability as spray dried compounds with the goal to optimize formulation of their delivery as a dry powder.
Aim 3 will test whether thiol- saccharides can effectively liquefy mucus in acute severe asthma.
Asthma exacerbations are a major public health problem, and mucus contributes significantly to the pathogens of asthma exacerbations. Available mucolytics have significant limitations of cost and convenience that restrict their application in practice. Or project proposes to address an unmet need for a well-tolerated and easily delivered mucolytic drug whose target of disulfide linkages make it relevant to diseases associated with heightened oxidative stress, including acute severe asthma.
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