The Marine Cyanobacterial Metabolite Gallinamide A Is a Potent and Selective Inhibitor of Human Cathepsin L

Title
The Marine Cyanobacterial Metabolite Gallinamide A Is a Potent and Selective Inhibitor of Human Cathepsin L
Author(s)
최혁재Bailey Miller[Bailey Miller]Aaron J. Friedman[Aaron J. Friedman]James Hogan[James Hogan]J. Anderew McCammon[J. Anderew McCammon]Vivian Hook[Vivian Hook]William H. Gerwick[William H. Gerwick]
Keywords
PK(A) VALUES; SECRETORY VESICLES; DOLASTATIN 10; PROTEIN; RATIONALIZATION; DISEASE; TARGET; CANCER; SIMULATIONS; PREDICTION
Issue Date
201401
Publisher
AMER CHEMICAL SOC
Citation
JOURNAL OF NATURAL PRODUCTS, v.77, no.1, pp.92 - 99
Abstract
A number of marine natural products are potent inhibitors of proteases, an important drug target class in human diseases. Hence, marine cyanobacterial extracts were assessed for inhibitory activity to human cathepsin L. Herein, we have shown that gallinamide A potently and selectively inhibits the human cysteine protease cathepsin L. With 30 min of preincubation, gallinamide A displayed an IC50 of 5.0 nM, and kinetic analysis demonstrated an inhibition constant of k(i) = 9000 +/- 260 M-1 s(-1) Preincubation-dilution and activity-probe experiments revealed an irreversible mode of inhibition, and comparative IC50 values display a 28- to 320-fold greater selectivity toward cathepsin L than closely related human cysteine cathepsin V or B. Molecular docking and molecular dynamics simulations were used to determine the pose of gallinamide in the active site of cathepsin L. These data resulted in the identification of a pose characterized by high stability, a consistent hydrogen bond network, and the reactive Michael acceptor enamide of gallinamide A positioned near the active site cysteine of the protease, leading to a proposed mechanism of covalent inhibition. These data reveal and characterize the novel activity of gallinamide A as a potent inhibitor of human cathepsin L.
URI
http://hdl.handle.net/YU.REPOSITORY/33480http://dx.doi.org/10.1021/np400727r
ISSN
0163-3864
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약학대학 > 약학부 > Articles
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