title: Inhibition of human neutrophil elastase by pentacyclic triterpenes.
abstract: METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Our results provide insights into the effects of pentacyclic triterpenes on lung inflammatory actions through reversible inhibition of HNE activity.
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Biological Chemistry, Second Military Medicinal University, Shanghai, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Fujiang
authors.initials: F
authors.lastname: Guo
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D053978:Pentacyclic Triterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011014:Pneumonia / Q000188:drug therapy; D066244:Proton Magnetic Resonance Spectroscopy; D012503:Saponins / Q000494:pharmacology / Q000627:therapeutic use; D012907:Smoking / Q000009:adverse effects; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000097245:Ursolic Acid
chemical_list: D004791:Enzyme Inhibitors; D005998:Glycine; D019272:Leukocyte Elastase; D053978:Pentacyclic Triterpenes; D012503:Saponins; D013449:Sulfonamides; D014315:Triterpenes; D000097245:Ursolic Acid; C052064:astragaloside A; C069195:sivelestat