Abstract
Light-regulated drugs allow remotely photoswitching biological activity and enable plausible therapies based on small molecules. However, only freely diffusible photochromic ligands have been shown to work directly in endogenous receptors and methods for covalent attachment depend on genetic manipulation. Here we introduce a chemical strategy to covalently conjugate and photoswitch the activity of endogenous proteins and demonstrate its application to the kainate receptor channel GluK1. The approach is based on photoswitchable ligands containing a short-lived, highly reactive anchoring group that is targeted at the protein of interest by ligand affinity. These targeted covalent photoswitches (TCPs) constitute a new class of light-regulated drugs and act as prosthetic molecules that photocontrol the activity of GluK1-expressing neurons, and restore photoresponses in degenerated retina. The modularity of TCPs enables the application to different ligands and opens the way to new therapeutic opportunities.
Highlights
Light-regulated drugs allow remotely photoswitching biological activity and enable plausible therapies based on small molecules
We describe here a new strategy to photoswitch protein activity that has the advantages of covalent attachment to the target but can be applied to endogenous proteins without requiring genetic manipulation
Our targeted covalent photoswitches (TCPs) afford kinetically controlled site-selective conjugation to lysine residues exposed on the protein surface in the vicinity of the ligand-binding site
Summary
Light-regulated drugs allow remotely photoswitching biological activity and enable plausible therapies based on small molecules. The approach is based on photoswitchable ligands containing a short-lived, highly reactive anchoring group that is targeted at the protein of interest by ligand affinity These targeted covalent photoswitches (TCPs) constitute a new class of light-regulated drugs and act as prosthetic molecules that photocontrol the activity of GluK1-expressing neurons, and restore photoresponses in degenerated retina. PCLs often display low specificity for a given molecular target, photoswitching is limited to a narrow concentration range and dilution in tissue reduces their efficacy and causes off-target effects To avoid these drawbacks of diffusible ligands, photocontrol can be confined to designated receptors and cells by means of photoisomerizable tethered ligands (PTLs) that are chemically attached to genetically engineered receptor proteins. TCPs enable photocontrolling the activity of neurons that endogenously express GluK1 and restore robust and sustained photoresponses in degenerated retina without genetic manipulation
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