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

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.