Photoactivatable Metabolic Warheads Enable Precise and Safe Ablation of Target Cells in Vivo
2020
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.
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