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PLoS One. 2013 Dec 20;8(12):e82794. doi: 10.1371/journal.pone.0082794. eCollection 2013.

Inhibition of human neutrophil elastase by pentacyclic triterpenes.

Author information

1
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2
Department of Biological Chemistry, Second Military Medicinal University, Shanghai, China.
3
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
4
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Abstract

SCOPE:

Inhibiting human neutrophil elastase (HNE) is a promising strategy for treating inflammatory lung diseases, such as H1N1 and SARS virus infections. The use of sivelestat, the only clinically registered synthesized HNE inhibitor, is largely limited by its risk of organ toxicity because it irreversibly inhibits HNE. Therefore, potent reversible HNE inhibitors are promising alternatives to sivelestat.

METHODS AND RESULTS:

An in vitro HNE inhibition assay was employed to screen a series of triterpenes. Six pentacyclic triterpenes, but not tetracyclic triterpenes, significantly inhibited HNE. Of these pentacyclic triterpenes, ursolic acid exhibited the highest inhibitory potency (IC50 = 5.51 µM). The HNE inhibitory activity of ursolic acid was further verified using a mouse model of acute smoke-induced lung inflammation. The results of nuclear magnetic resonance and HNE inhibition kinetic analysis showed that the pentacyclic triterpenes competitively and reversibly inhibited HNE. Molecular docking experiments indicated that the molecular scaffold, 28-COOH, and a double bond at an appropriate location in the pentacyclic triterpenes are important for their inhibitory activity.

CONCLUSION:

Our results provide insights into the effects of pentacyclic triterpenes on lung inflammatory actions through reversible inhibition of HNE activity.

PMID:
24376583
PMCID:
PMC3869726
DOI:
10.1371/journal.pone.0082794
[Indexed for MEDLINE]
Free PMC Article

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