On the Process of Discovering Leads That Target the Heparin-Binding Site of Neutrophil Elastase in the Sputum of Cystic Fibrosis Patients.

J Med Chem 2019 06 28;62(11):5501-5511. Epub 2019 May 28.

Department of Medicinal Chemistry , Virginia Commonwealth University , Richmond , Virginia 23298 , United States.

Cystic fibrosis (CF) is a disease of dysregulated salt and fluid homeostasis that results in the massive accumulation of neutrophil elastase, resulting in lung degradation and death. The current CF therapy relies on inhaled deoxyribonuclease and hypertonic saline but does not address the elastolytic degradation of the lung. We reasoned that allosteric agents targeting the heparin-binding site of neutrophil elastase would offer a therapeutic paradigm. Screening a library of 60 nonsaccharide glycosaminoglycan mimetics (NSGMs) led to the discovery of 23 hits against neutrophil elastase. To identify a lead NSGM that works in sync with the current CF-relieving agents, we developed a rigorous protocol based on fundamental computational, biochemical, mechanistic, and adverse effect studies. The lead NSGM so identified neutralized neutrophil elastase present in the sputum of CF patients in the presence of deoxyribonuclease and high-salt conditions. Our work presents the process for discovering potent, small, synthetic, allosteric, anti-CF agents, while also identifying a novel lead for further studies in animal models of CF.

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http://dx.doi.org/10.1021/acs.jmedchem.9b00379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818412PMC
June 2019
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