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Light Activation of a Cysteine Protease Inhibitor: Caging of a Peptidomimetic Nitrile with RuII(bpy)2

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journal contribution
posted on 02.11.2011, 00:00 authored by Tomasz Respondek, Robert N. Garner, Mackenzie K. Herroon, Izabela Podgorski, Claudia Turro, Jeremy J. Kodanko
A novel method for caging protease inhibitors is described. The complex [RuII(bpy)2(1)2](PF6)2 (2) was prepared from the nitrile-based peptidomimetic inhibitor Ac-Phe-NHCH2CN (1). 1H NMR, UV–vis, and IR spectroscopic and mass spectrometric data confirmed that 2 equiv of inhibitor 1 bind to RuII through the nitrile functional group. Complex 2 shows excellent stability in aqueous solution in the dark and fast release of 1 upon irradiation with visible light. As a result of binding to the RuII center, the nitriles of complex 2 are caged, and 2 does not act as a potent enzyme inhibitor. However, when 2 is irradiated, it releases 1, which inhibits the cysteine proteases papain and cathepsins B, K and L up to 2 times more potently than 1 alone. Ratios of the IC50 values in the dark versus in the light ranged from 6:1 to 33:1 for inhibition by 2 against isolated enzymes and in human cell lysates, confirming that a high level of photoinduced enzyme inhibition can be obtained using this method.