Issue 36, 2021

Photoaffinity labelling strategies for mapping the small molecule–protein interactome

Abstract

Nearly all FDA approved drugs and bioactive small molecules exert their effects by binding to and modulating proteins. Consequently, understanding how small molecules interact with proteins at an molecular level is a central challenge of modern chemical biology and drug development. Complementary to structure-guided approaches, chemoproteomics has emerged as a method capable of high-throughput identification of proteins covalently bound by small molecules. To profile noncovalent interactions, established chemoproteomic workflows typically incorporate photoreactive moieties into small molecule probes, which enable trapping of small molecule-protein interactions (SMPIs). This strategy, termed photoaffinity labelling (PAL), has been utilized to profile an array of small molecule interactions, including for drugs, lipids, metabolites, and cofactors. Herein we describe the discovery of photocrosslinking chemistries, including a comparison of the strengths and limitations of implementation of each chemotype in chemoproteomic workflows. In addition, we highlight key examples where photoaffinity labelling has enabled target deconvolution and interaction site mapping.

Graphical abstract: Photoaffinity labelling strategies for mapping the small molecule–protein interactome

Article information

Article type
Review Article
Submitted
12 Jul 2021
Accepted
18 Ago 2021
First published
19 Ago 2021

Org. Biomol. Chem., 2021,19, 7792-7809

Photoaffinity labelling strategies for mapping the small molecule–protein interactome

N. R. Burton, P. Kim and K. M. Backus, Org. Biomol. Chem., 2021, 19, 7792 DOI: 10.1039/D1OB01353J

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