title: Trivaric acid, a potent depside human leukocyte elastase inhibitor.
abstract: Human leukocyte elastase (HLE) is a serine protease implicated in several inflammatory diseases, and represents a major target for anti-inflammatory drug development. In the present study, nordivaricatic acid (1), divarinyl divarate (2), and trivaric acid (3), three depsides isolated from the culture of a soil derived fungal strain were identified as inhibitors of HLE. Two didepsides 1 and 2 showed low inhibitory activity. In contrast, trivaric acid, a para-tridepside, exhibited highly potent inhibitory activity with an IC(50) value of 1.8 µM and a K(i) of 0.6 µM. Kinetic investigations with trivaric acid showed that this inhibition is reversible, competitive pattern. Further studies on the selectivity of three depsides toward serine proteases showed that they did not inhibit chymotrypsin, trypsin and thrombin even at 150 µM.
authors.affiliation: New Drug Research & Development Center, North China Pharmaceutical Group Corporation, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zheng
authors.forename: Shen
authors.initials: S
authors.lastname: Zhang
authors.forename: Xinhua
authors.initials: X
authors.lastname: Lu
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.forename: Yuling
authors.initials: Y
authors.lastname: Fan
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.forename: Aihua
authors.initials: A
authors.lastname: Dong
authors.forename: Baoling
authors.initials: B
authors.lastname: Duan
mesh_terms: D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology*; D053630:Depsides / Q000302:isolation & purification / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D005658:Fungi / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D012988:Soil Microbiology
chemical_list: D001688:Biological Products; D053630:Depsides; D004791:Enzyme Inhibitors; C581105:trivaric acid; D019272:Leukocyte Elastase