7lcu | pdb_00007lcu
X-ray structure of Furin bound to BOS-318, a small molecule inhibitor
Structural highlights
FunctionFURIN_HUMAN Furin is likely to represent the ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RX(K/R)R consensus motif.[1] Publication Abstract from PubMedIn cystic fibrosis (CF), excessive furin activity plays a critical role in the activation of the epithelial sodium channel (ENaC), dysregulation of which contributes to airway dehydration, ineffective mucociliary clearance (MCC), and mucus obstruction. Here, we report a highly selective, cell-permeable furin inhibitor, BOS-318, that derives selectivity by eliciting the formation of a new, unexpected binding pocket independent of the active site catalytic triad. Using human ex vivo models, BOS-318 showed significant suppression of ENaC, which led to enhanced airway hydration and an approximately 30-fold increase in MCC rate. Furin inhibition also protected ENaC from subsequent activation by neutrophil elastase, a soluble protease dominant in CF airways. Additional therapeutic benefits include protection against epithelial cell death induced by Pseudomonas aeruginosa exotoxin A. Our findings demonstrate the utility of selective furin inhibition as a mutation-agnostic approach that can correct features of CF airway pathophysiology in a manner expected to deliver therapeutic value. A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of cystic fibrosis airway disease.,Douglas LEJ, Reihill JA, Ho MWY, Axten JM, Campobasso N, Schneck JL, Rendina AR, Wilcoxen KM, Martin SL Cell Chem Biol. 2022 Jun 16;29(6):947-957.e8. doi:, 10.1016/j.chembiol.2022.02.001. Epub 2022 Feb 23. PMID:35202587[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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