Issue 5, 2020

Xanthine-based photoaffinity probes allow assessment of ligand engagement by TRPC5 channels

Abstract

TRPC1/4/5 cation channels are emerging drug targets for the treatment of, amongst others, central nervous system (CNS) disorders, kidney disease, and cardiovascular and metabolic disease. Various small-molecule TRPC1/4/5 modulators have been reported, including highly potent xanthine derivatives that distinguish between specific TRPC1/4/5 tetramers. However, tools to profile ligand engagement by TRPC1/4/5 channels in live cells are lacking. Here, we report a set of potent xanthine-based photoaffinity probes that functionally mimic the xanthines Pico145 and AM237. Using these probes, we have developed a photoaffinity labelling protocol for TRPC5 channels, providing the first method for the quantitative assessment of binding interactions of TRPC5 with small molecules in cells. This method could be important for drug discovery efforts targeting the xanthine/lipid binding site of TRPC1/4/5 channels.

Graphical abstract: Xanthine-based photoaffinity probes allow assessment of ligand engagement by TRPC5 channels

Supplementary files

Article information

Article type
Paper
Submitted
15 Jul 2020
Accepted
11 Sep 2020
First published
18 Sep 2020
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2020,1, 436-448

Xanthine-based photoaffinity probes allow assessment of ligand engagement by TRPC5 channels

C. C. Bauer, A. Minard, I. B. Pickles, K. J. Simmons, E. Chuntharpursat-Bon, M. P. Burnham, N. Kapur, D. J. Beech, S. P. Muench, M. H. Wright, S. L. Warriner and R. S. Bon, RSC Chem. Biol., 2020, 1, 436 DOI: 10.1039/D0CB00126K

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