Aryl azopyrroles as visible light photoswitchable TRPA1 ligands

Abstract

Access to high quality optochemogenetic tools will enable precise interrogation of the complex biology of diverse cell types, allowing temporally and spatially controlled manipulation of cell autonomous functions. This level of control is expected to yield deeper mechanistic insights and foster the development of targeted strategies and molecular interventions for translational photopharmacology. Recent years have demonstrated the exciting potential of heteroaromatic azoarene photoswitches, particularly to tune azo photoswitch performance. However, strategies to integrate such motifs into photopharmacological ligands remain underdeveloped. Leveraging a previously developed screening assay, we report the discovery of a robust aryl azopyrrole ligand for the TRPA1 channel, TRPswitch-C. TRPswitch-C provides a red-shifted chemotype to address this channel, allowing optical control in live zebrafish larvae in a controllable fashion. Not only does this study expand the tool kit for optochemogenetic experiments using TRPA1, but also advocates the further exploration of heteroaromatic azoarenes in photopharmacology.