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

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  • Mercè Izquierdo-Serra

    (Institut de Bioenginyeria de Catalunya (IBEC)
    Present address: Department de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain.)

  • Antoni Bautista-Barrufet

    (Institut de Bioenginyeria de Catalunya (IBEC)
    Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology
    Present address: Institute of Molecular Sciences (Bordeaux University), 33405 Bordeaux, France.)

  • Ana Trapero

    (Institut de Bioenginyeria de Catalunya (IBEC)
    Institut de Química Avançada de Catalunya (IQAC-CSIC)
    Present address: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.)

  • Aida Garrido-Charles

    (Institut de Bioenginyeria de Catalunya (IBEC))

  • Ariadna Díaz-Tahoces

    (Instituto de Bioingeniería, Universidad Miguel Hernández (UMH))

  • Nuria Camarero

    (Institut de Bioenginyeria de Catalunya (IBEC))

  • Silvia Pittolo

    (Institut de Bioenginyeria de Catalunya (IBEC))

  • Sergio Valbuena

    (Instituto de Neurociencias (CSIC-UMH))

  • Ariadna Pérez-Jiménez

    (Institut de Bioenginyeria de Catalunya (IBEC))

  • Marina Gay

    (Institut de Recerca en Biomedicina (IRBB))

  • Alejandro García-Moll

    (Instituto de Bioingeniería, Universidad Miguel Hernández (UMH))

  • Carles Rodríguez-Escrich

    (Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology)

  • Juan Lerma

    (Instituto de Neurociencias (CSIC-UMH))

  • Pedro de la Villa

    (Universidad de Alcalá de Henares (UAH))

  • Eduardo Fernández

    (Instituto de Bioingeniería, Universidad Miguel Hernández (UMH)
    Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN))

  • Miquel À Pericàs

    (Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology
    Departament de Química Inorgànica i Orgànica, Universitat de Barcelona (UB))

  • Amadeu Llebaria

    (Institut de Química Avançada de Catalunya (IQAC-CSIC))

  • Pau Gorostiza

    (Institut de Bioenginyeria de Catalunya (IBEC)
    Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN)
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

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.

Suggested Citation

  • Mercè Izquierdo-Serra & Antoni Bautista-Barrufet & Ana Trapero & Aida Garrido-Charles & Ariadna Díaz-Tahoces & Nuria Camarero & Silvia Pittolo & Sergio Valbuena & Ariadna Pérez-Jiménez & Marina Gay & , 2016. "Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12221
    DOI: 10.1038/ncomms12221
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