Abstract
Advances in high-throughput screening now enable the rapid discovery of bioactive small molecules, but these primary hits almost always exhibit modest potency. We report a strategy for the transformation of these hits into much more potent inhibitors without compound optimization. Appending a derivative of Ru(II)(tris-bipyridyl)2+, an efficient photosensitizer of singlet oxygen production, to synthetic protein-binding compounds results in highly potent and specific target protein inactivation upon irradiation with visible light.
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Acknowledgements
This work was supported by a contract from the US National Heart, Lung, and Blood Institute (NO1-HV28185) for the University of Texas Southwestern Center for Proteomics Research. We thank M. Rosen (University of Texas Southwestern) and B. Cravatt (The Scripps Research Institute) for a critical reading of the manuscript.
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J.L. designed and performed experiments, analyzed data and wrote the manuscript. D.G.U. and H.-S.L. performed experiments. T.K. designed experiments, analyzed data and wrote the manuscript.
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Lee, J., Udugamasooriya, D., Lim, HS. et al. Potent and selective photo-inactivation of proteins with peptoid-ruthenium conjugates. Nat Chem Biol 6, 258–260 (2010). https://doi.org/10.1038/nchembio.333
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DOI: https://doi.org/10.1038/nchembio.333
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