Photoactivatable metabolic warheads enable precise and safe ablation of target cells in vivo

Sam Benson, Fabio Moliner, Antonio Fernandez, Erkin Kuru, Nicholas L. Asiimwe, Jun-Seok Lee, Lloyd Hamilton, Dirk Sieger, Isabel R. Bravo, Abigail M. Elliot, Yi Feng () and Marc Vendrell ()
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Sam Benson: The University of Edinburgh
Fabio Moliner: The University of Edinburgh
Antonio Fernandez: The University of Edinburgh
Erkin Kuru: Harvard Medical School
Nicholas L. Asiimwe: Molecular Recognition Research Center, Korea Institute of Science and Technology (KIST) & Bio-Med Program KIST-School UST
Jun-Seok Lee: Korea University College of Medicine
Lloyd Hamilton: The University of Edinburgh
Dirk Sieger: The University of Edinburgh
Isabel R. Bravo: The University of Edinburgh
Abigail M. Elliot: The University of Edinburgh
Yi Feng: The University of Edinburgh
Marc Vendrell: The University of Edinburgh

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 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 photoactivatable probes 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 tools to exploit cellular metabolic signatures for safer therapeutic and surgical approaches.

Date: 2021
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DOI: 10.1038/s41467-021-22578-2

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