2. Academic Validation
  3. Photoactivatable metabolic warheads enable precise and safe ablation of target cells in vivo

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

  • Nat Commun. 2021 Apr 22;12(1):2369. doi: 10.1038/s41467-021-22578-2.
Sam Benson 1,  Fabio de Moliner 1,  Antonio Fernandez 1,  Erkin Kuru 2 3,  Nicholas L Asiimwe 4,  Jun-Seok Lee 5,  Lloyd Hamilton 6,  Dirk Sieger 6,  Isabel R Bravo 1,  Abigail M Elliot 1,  Yi Feng 7,  Marc Vendrell 8
Affiliations

Affiliations

  • 1 Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
  • 2 Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • 3 Wyss Institute for Biologically Inspired Engineering, Boston, MA, USA.
  • 4 Molecular Recognition Research Center, Korea Institute of Science and Technology (KIST) & Bio-Med Program KIST-School UST, Seoul, South Korea.
  • 5 Department of Pharmacology, Korea University College of Medicine, Seoul, South Korea.
  • 6 The Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, UK.
  • 7 Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK. yi.feng@ed.ac.uk.
  • 8 Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK. marc.vendrell@ed.ac.uk.
PMID: 33888691 DOI: 10.1038/s41467-021-22578-2
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.

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