Document Detail

Potent elastase inhibitors from cyanobacteria: structural basis and mechanisms mediating cytoprotective and anti-inflammatory effects in bronchial epithelial cells.
MedLine Citation:
PMID:  23350733     Owner:  NLM     Status:  MEDLINE    
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.
Lilibeth A Salvador; Kanchan Taori; Jason S Biggs; Jean Jakoncic; David A Ostrov; Valerie J Paul; Hendrik Luesch
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-28
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-15     Completed Date:  2013-04-19     Revised Date:  2014-02-17    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1276-90     Citation Subset:  IM    
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MeSH Terms
Anti-Inflammatory Agents / pharmacology*
Bronchi / cytology,  drug effects*
Cell Line
Crystallography, X-Ray
Cyanobacteria / chemistry*
Enzyme Inhibitors / isolation & purification,  pharmacology*
Epithelial Cells / drug effects
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Structure
Pancreatic Elastase / antagonists & inhibitors*
Real-Time Polymerase Chain Reaction
Spectrometry, Mass, Electrospray Ionization
Grant Support
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Enzyme Inhibitors; EC Elastase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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