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Nat Commun. 2016 Jul 20;7:12221. doi: 10.1038/ncomms12221.

Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches.

Author information

1
Institut de Bioenginyeria de Catalunya (IBEC), Barcelona 08028, Spain.
2
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Tarragona 43007, Spain.
3
Institut de Química Avançada de Catalunya (IQAC-CSIC), Barcelona 08034, Spain.
4
Instituto de Bioingeniería, Universidad Miguel Hernández (UMH), Elche 03202, Spain.
5
Instituto de Neurociencias (CSIC-UMH), San Juan de Alicante 03550, Spain.
6
Institut de Recerca en Biomedicina (IRBB), Barcelona 08028, Spain.
7
Universidad de Alcalá de Henares (UAH), Alcalá de Henares 28871, Spain.
8
Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza 50018, Spain.
9
Departament de Química Inorgànica i Orgànica, Universitat de Barcelona (UB), Barcelona 08007, Spain.
10
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.

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.

PMID:
27436051
PMCID:
PMC4961765
DOI:
10.1038/ncomms12221
[Indexed for MEDLINE]
Free PMC Article

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