The marine cyanobacterial metabolite gallinamide a is a potent and selective inhibitor of human cathepsin l

TitleThe marine cyanobacterial metabolite gallinamide a is a potent and selective inhibitor of human cathepsin l
Publication TypeJournal Article
Year of Publication2014
AuthorsMiller B., Friedman A.J, Choi H., Hogan J., McCammon J.A, Hook V., Gerwick WH
JournalJournal of Natural Products
Volume77
Pagination92-99
Date Published2014/01
Type of ArticleArticle
ISBN Number0163-3864
Accession NumberWOS:000330336800015
Keywordscancer; disease; dolastatin 10; pk(a) values; prediction; protein; rationalization; secretory vesicles; simulations; target
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.

DOI10.1021/np400727r
Short TitleJ. Nat. Prod.
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