The use of BOS-318 in human ex vivo models has shown an increase in airway hydration, mucociliary clearance, and protection against epithelial cell death due to Pseudomonas aeruginosa infection, therefore suggesting a potential therapeutic value in cystic fibrosis (CF), as published in Cell Chemical Biology.

The pathogenesis of CF is associated with an epithelial sodium channel (ENaC) dysfunction, which causes excessive sodium reabsorption, leading to airway dehydration with a decreased layer of airway surface liquid, which is vital for the process of mucociliary clearance (MCC).

BOS-318 is a selective furin inhibitor, and furin is a proprotein protease proven to be excessively active in CF. Among other stimuli such as channel activating proteases and neutrophil elastase, furin plays an important role in activating the ENaC. Consequently, researchers believe that a decrease in its activity may lead to therapeutic benefits in CF.

An excessive furin activity is not only reported in CF. Several studies associate it with certain types of cancer as well as in the pathogenesis of SARS-CoV-2 responsible for the global pandemic. 

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BOS-318 was discovered from DNA encoded library technology and advanced medical chemistry. It is a cell permeable, highly selective furin inhibitor that binds directly to its active cleft. It has proven to dramatically decrease sodium absorption by ENaC in human bronchial epithelial cells without having any negative effect on cell viability (measured by an increase in lactic acid concentration). The inhibitory effect over ENaC persisted when purified neutrophil elastase was added to the cell.

The ENaC inhibition correlated with an increase in both airway surface liquid and MCC. The authors reported a 35% increase in the height of airway surface liquid and a 30-fold increase in MCC in the presence of BOS-318.

BOS-318 also proved to be protective against P aeruginosa endotoxin A (PEA). Researchers treated cells with PEA both in the presence and absence of BOS-318. After 72 hours, cell viability in the presence of the furin inhibitor increased by more than 80%.

“Our findings demonstrate the utility of selective furin inhibition, such as that mediated by BOS-318, to correct fundamental features of CF airway pathophysiology in a manner expected to deliver therapeutic value,” the authors concluded. 

Reference

Douglas LEJ, Reihill JA, Ho MWY, et al. A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of cystic fibrosis airway disease. Cell Chem Biol. Published online June 16, 2022. doi:10.1016/j.chembiol.2022.02.001