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Potent and selective photo-inactivation of proteins with peptoid-ruthenium conjugates

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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Figure 1: Visible light–triggered inactivation of VEGFR2 by a ruthenium-peptoid conjugate.
Figure 2: A hyperpotent CALI inhibitor of VEGFR2.
Figure 3: Visible light–triggered inactivation of the 26S proteasome by a ruthenium-peptoid conjugate.

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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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Authors

Contributions

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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Correspondence to Thomas Kodadek.

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The authors declare no competing financial interests.

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Supplementary Methods and Supplementary Figures 1–15 (PDF 827 kb)

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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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