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

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• 作者：Bailey Miller ; Aaron J. Friedman ; Hyukjae Choi ; James Hogan ; J. Andrew McCammon ; Vivian Hook ; William H. Gerwick
• 刊名：Journal of Natural Products
• 出版年：2014
• 出版时间：January 24, 2014
• 年：2014
• 卷：77
• 期：1
• 页码：92-99
• 全文大小：380K
• ISSN：1520-6025

文摘

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 卤 260 M^鈥? s^鈥?. Preincubation鈥揹ilution 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.