Inhibition of s-nitrosoglutathione reductase for the treatment of asthma

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DESCRIPTION (provided by applicant): Asthma is a disorder arising from chronic inflammation of the airways. The inflamed airways become hyper-responsive to various inhaled stimuli and become obstructed as result of contraction of bronchial smooth muscles. Depletion of the endogenous bronchodilator, s-nitrosoglutathione (GSNO) from the airways of asthmatics and experimental animals suggested that one of the underlying causes of airflow obstruction to be the loss of GSNO from the airway lining fluid. This has been supported by studies in mice deficient in GSNO metabolizing enzyme, s-nitrosoglutathione reductase (GSNOR). Mice deficient in GSNOR were protected from airway hyper-responsivity even in presence of strong inflammation. The long term objective of the current study is to design inhibitors of human GSNOR and evaluate the usefulness of preventing GSNO breakdown in the treatment of asthma. We will use high throughput screening methods to identify compounds that bind human GSNOR. We will further evaluate the potential of the identified compounds as leads for investigating the effects of GSNOR inhibition on airway hyper-responsivity using enzyme kinetics, x-ray crystallography and measurement of changes in the protein s-nitrosylation levels in a cell culture model. The proposed work will lead to identification of compounds that will allow evaluating a new approach for preventing asthmatic episodes in asthma patients.