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Photoactivatable Metabolic Warheads Enable Precise and Safe Ablation of Target Cells in Vivo

preprint
submitted on 10.11.2020, 17:35 and posted on 12.11.2020, 12:44 by Sam Benson, Fabio de Moliner, Antonio Fernandez, Erkin Kuru, Nicholas Asiimwe, Jun-Seok Lee, Lloyd Hamilton, Dirk Sieger, Isabel Ribeiro Bravo, Abigail Elliot, Yi Feng, Marc Vendrell
Photoactivatable molecules enable ablation of malignant cells under the control of light, yet current agents can be ineffective at early stages of disease when target cells are similar to healthy surrounding tissues. In this work, we describe a chemical platform based on amino-substituted benzoselenadiazoles to build photosensitizers that mimic native metabolites as indicators of disease onset and progression. Through a series of synthetic derivatives, we have identified the key chemical groups in the benzoselenadiazole scaffold responsible for its photodynamic activity, and subsequently designed photosensitive metabolic warheads to target cells associated with various diseases, including bacterial infections and cancer. We demonstrate that versatile benzoselenadiazole metabolites can selectively kill pathogenic cells -but not healthy cells- with high precision after exposure to non-toxic visible light, reducing any potential side effects in vivo. This chemical platform provides powerful new tools to exploit cellular metabolic signatures for safer therapeutic and surgical approaches.

Funding

Medical Research Scotland - 879-2015

MSCA Individual Fellowship - 704912

Wellcome Trust Sir Henry Dale Fellowship -100104/Z/12/Z

Cancer Research UK Early Detection Award -C38363/A26931

Medical Research Council - MR/N013166/1

ERC Consolidator Grant - 771443

History

Email Address of Submitting Author

marc.vendrell@ed.ac.uk

Institution

University of Edinburgh

Country

United Kingdom

ORCID For Submitting Author

0000-0002-5392-9740

Declaration of Conflict of Interest

The University of Edinburgh has filed a patent covering some of the technology described in this manuscript.

Version Notes

Version 1.0

Licence

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