Potent elastase inhibitors from cyanobacteria: structural basis and mechanisms mediating cytoprotective and anti-inflammatory effects in bronchial epithelial cells.
We discovered new structural diversity to a prevalent, yet medicinally underappreciated, cyanobacterial protease inhibitor scaffold and undertook comprehensive protease profiling to reveal potent and selective elastase inhibition. Structure-activity relationship (SAR) studies and X-ray cocrystal structure analysis allowed a detailed assessment of critical and tunable structural elements. To realize the therapeutic potential of these cyclodepsipeptides, we probed the cellular effects of a novel and representative family member, symplostatin 5 (1), which attenuated the downstream cellular effects of elastase in an epithelial lung airway model system, alleviating clinical hallmarks of chronic pulmonary diseases such as cell death, cell detachment, and inflammation. This compound attenuated the effects of elastase on receptor activation, proteolytic processing of the adhesion protein ICAM-1, NF-κB activation, and transcriptomic changes, including the expression of pro-inflammatory cytokines IL1A, IL1B, and IL8. Compound 1 exhibited activity comparable to the clinically approved elastase inhibitor sivelestat in short-term assays and demonstrated superior sustained activity in longer-term assays.
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, USA.
Lilibeth A
LA
Salvador
Kanchan
K
Taori
Jason S
JS
Biggs
Jean
J
Jakoncic
David A
DA
Ostrov
Valerie J
VJ
Paul
Hendrik
H
Luesch
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects*; D002460:Cell Line; D018360:Crystallography, X-Ray; D000458:Cyanobacteria / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D060888:Real-Time Polymerase Chain Reaction; D021241:Spectrometry, Mass, Electrospray Ionization
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D010196:Pancreatic Elastase