Photoactivatable metabolic warheads enable precise and safe ablation of target cells in vivo Benson, Sam de Moliner, Fabio Fernández Vargas, Antonio Jesús Kuru, Erkin Asiimwe, Nicholas L Lee, Jun-Seok Hamilton, Lloyd Sieger, Dirk Bravo, Isabel R Elliot, Abigail M Feng, Yi Vendrell, Marc 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 aminosubstituted 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. 2025-01-09T11:17:34Z 2025-01-09T11:17:34Z 2021-04-22 journal article Benson, S., de Moliner, F., Fernandez, A. et al. Photoactivatable metabolic warheads enable precise and safe ablation of target cells in vivo. Nat Commun 12, 2369 (2021). https://doi.org/10.1038/s41467-021-22578-2 https://hdl.handle.net/10481/98765 https://doi.org/10.1038/s41467-021-22578-2 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional