Open Access2-Aryl-5-carboxytetrazole as a New Photoaffinity Label for Drug Target Identification
Author(s) -
András Herner,
Jasmina Marjanovic,
Tracey M. Lewandowski,
Violeta L. Marin,
Melanie J. Patterson,
Laura J. Miesbauer,
Damien Ready,
Jon D. Williams,
Anil Vasudevan,
Qing Lin
Publication year - 2016
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.6b06645
Subject(s) - diazirine , chemistry , photoaffinity labeling , benzophenone , ligand (biochemistry) , aryl , combinatorial chemistry , drug discovery , stereochemistry , imine , binding site , biochemistry , photochemistry , receptor , organic chemistry , alkyl , catalysis
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.