2-Aryl-5-carboxytetrazole as a New Photoaffinity Label for Drug Target Identification
| Autor: | András Herner, Qing Lin, Laura Miesbauer, Violeta L. Marin, Melanie J. Patterson, Damien B. Ready, Jasmina Marjanovic, Jon D. Williams, Tracey M. Lewandowski, Anil Vasudevan |
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| Rok vydání: | 2016 |
| Předmět: |
Proteomics
Stereochemistry Imine Dasatinib Tetrazoles Photoaffinity Labels 010402 general chemistry 01 natural sciences Biochemistry Catalysis Fluorescence Article chemistry.chemical_compound Colloid and Surface Chemistry Drug Delivery Systems Tandem Mass Spectrometry Benzophenone Humans Amino Acid Sequence biology Molecular Structure 010405 organic chemistry Drug discovery Active site Computational Biology General Chemistry Ligand (biochemistry) Combinatorial chemistry 0104 chemical sciences chemistry Diazirine biology.protein Target protein K562 Cells |
| Zdroj: | Journal of the American Chemical Society |
| ISSN: | 1520-5126 |
| Popis: | Photoaffinity labels are powerful tools for dissecting ligand–protein interactions, and they have a broad utility in medicinal chemistry and drug discovery. Traditional photoaffinity labels work through nonspecific C–H/X–H bond insertion reactions with the protein of interest by the highly reactive photogenerated intermediate. Herein, we report a new photoaffinity label, 2-aryl-5-carboxytetrazole (ACT), that interacts with the target protein via a unique mechanism in which the photogenerated carboxynitrile imine reacts with a proximal nucleophile near the target active site. In two distinct case studies, we demonstrate that the attachment of ACT to a ligand does not significantly alter the binding affinity and specificity of the parent drug. Compared with diazirine and benzophenone, two commonly used photoaffinity labels, in two case studies ACT showed higher photo-cross-linking yields toward their protein targets in vitro based on mass spectrometry analysis. In the in situ target identification studies, ACT successfully captured the desired targets with an efficiency comparable to the diazirine. We expect that further development of this class of photoaffinity labels will lead to a broad range of applications across target identification, and validation and elucidation of the binding site in drug discovery. |
| Databáze: | OpenAIRE |
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