Journal
JOURNAL OF NATURAL PRODUCTS
Volume 77, Issue 1, Pages 92-99Publisher
AMER CHEMICAL SOC
DOI: 10.1021/np400727r
Keywords
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Funding
- NIH [T32DA007315, NIH T32GM007752, NIH FIC U01 TW006634, NIH R01MH077305, NIH 5T32GM007752-32, NIH GM31749]
- USDA [2008-35621-04749]
- Howard Hughes Medical Institute
- NSF Supercomputer Centers
- San Diego Supercomputer Center
- W.M. Keck Foundation
- National Biomedical Computational Resource
- Center for Theoretical Biological Physics
- NSF [MCB-1020765, MCA93S013]
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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.
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