Targeted activation in localized protein environments via deep red photoredox catalysis

• Published in: Nature chemistry Vol. 15; no. 1; pp. 101 - 109
• Main Authors: Tay, Nicholas Eng Soon, Ryu, Keun Ah, Weber, John L., Olow, Aleksandra K., Cabanero, David C., Reichman, David R., Oslund, Rob C., Fadeyi, Olugbeminiyi O., Rovis, Tomislav
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2023; NATURE PORTFOLIO; Nature Publishing Group
• Subjects: 631/92/96; 639/638/403/933; 639/638/77/890; Analytical Chemistry; Aromatic compounds; Biochemistry; Biological activity; Catalysis; Cell adhesion; Cell adhesion molecules; Chemistry; Chemistry and Materials Science; Chemistry, Multidisciplinary; Chemistry/Food Science; Colon cancer; Colonic Neoplasms; Colorectal cancer; Epithelial Cell Adhesion Molecule; Epithelial cells; Epithelium; Humans; Inorganic Chemistry; Labeling; Light; Microenvironments; Organic Chemistry; Organic compounds; Peptide mapping; Photoactivation; Photocatalysis; Photocatalysts; Photoredox catalysis; Physical Chemistry; Physical Sciences; Proteins; Science & Technology; Substrates; Tumors; LIFETIMES; SPECTROSCOPY; KINETICS; CHEMISTRY; PHOTOCHEMISTRY; ARYL AZIDES; PHOTOLYSIS; NITRENES
• ISSN: 1755-4330; 1755-4349; 1755-4349
• DOI: 10.1038/s41557-022-01057-1

State-of-the-art photoactivation strategies in chemical biology provide spatiotemporal control and visualization of biological processes. However, using high-energy light ( λ  < 500 nm) for substrate or photocatalyst sensitization can lead to background activation of photoactive small-molecule probes and reduce its efficacy in complex biological environments. Here we describe the development of targeted aryl azide activation via deep red-light ( λ  = 660 nm) photoredox catalysis and its use in photocatalysed proximity labelling. We demonstrate that aryl azides are converted to triplet nitrenes via a redox-centric mechanism and show that its spatially localized formation requires both red light and a photocatalyst-targeting modality. This technology was applied in different colon cancer cell systems for targeted protein environment labelling of epithelial cell adhesion molecule (EpCAM). We identified a small subset of proteins with previously known and unknown association to EpCAM, including CDH3, a clinically relevant protein that shares high tumour-selective expression with EpCAM. Technologies for profiling biological environments with high spatiotemporal resolution are in demand to enable the discovery of new targets for addressing unmet clinical needs. Now, a deep red light-mediated photocatalytic strategy for the targeted activation of aryl azides has been developed. This platform enables mapping of protein microenvironments in physiologically relevant systems.