title: Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches.
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.
authors.affiliation: Institut de Bioenginyeria de Catalunya (IBEC), Barcelona 08028, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Izquierdo-Serra
authors.affiliation: Institut de Bioenginyeria de Catalunya (IBEC), Barcelona 08028, Spain.|Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Tarragona 43007, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Bautista-Barrufet
authors.affiliation: Institut de Bioenginyeria de Catalunya (IBEC), Barcelona 08028, Spain.|Institut de Química Avançada de Catalunya (IQAC-CSIC), Barcelona 08034, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Trapero
authors.affiliation: Institut de Bioenginyeria de Catalunya (IBEC), Barcelona 08028, Spain.
authors.forename: Aida
authors.initials: A
authors.lastname: Garrido-Charles
authors.affiliation: Instituto de Bioingeniería, Universidad Miguel Hernández (UMH), Elche 03202, Spain.
authors.forename: Ariadna
authors.initials: A
authors.lastname: Díaz-Tahoces
authors.affiliation: Institut de Bioenginyeria de Catalunya (IBEC), Barcelona 08028, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Camarero
authors.affiliation: Institut de Bioenginyeria de Catalunya (IBEC), Barcelona 08028, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pittolo
authors.affiliation: Instituto de Neurociencias (CSIC-UMH), San Juan de Alicante 03550, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Valbuena
authors.affiliation: Institut de Bioenginyeria de Catalunya (IBEC), Barcelona 08028, Spain.
authors.forename: Ariadna
authors.initials: A
authors.lastname: Pérez-Jiménez
authors.affiliation: Institut de Recerca en Biomedicina (IRBB), Barcelona 08028, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Gay
authors.affiliation: Instituto de Bioingeniería, Universidad Miguel Hernández (UMH), Elche 03202, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: García-Moll
authors.affiliation: Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Tarragona 43007, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Rodríguez-Escrich
authors.affiliation: Instituto de Neurociencias (CSIC-UMH), San Juan de Alicante 03550, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Lerma
authors.affiliation: Universidad de Alcalá de Henares (UAH), Alcalá de Henares 28871, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: de la Villa
authors.affiliation: Instituto de Bioingeniería, Universidad Miguel Hernández (UMH), Elche 03202, Spain.|Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza 50018, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernández
authors.affiliation: Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Tarragona 43007, Spain.|Departament de Química Inorgànica i Orgànica, Universitat de Barcelona (UB), Barcelona 08007, Spain.
authors.forename: Miquel À
authors.initials: MÀ
authors.lastname: Pericàs
authors.affiliation: Institut de Química Avançada de Catalunya (IQAC-CSIC), Barcelona 08034, Spain.
authors.forename: Amadeu
authors.initials: A
authors.lastname: Llebaria
authors.affiliation: Institut de Bioenginyeria de Catalunya (IBEC), Barcelona 08028, Spain.|Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza 50018, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
authors.forename: Pau
authors.identifier: 0000-0002-7268-5577
authors.initials: P
authors.lastname: Gorostiza
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057930:Click Chemistry; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007536:Isomerism; D008024:Ligands; D008027:Light; D051379:Mice; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism; D055095:Optics and Photonics / Q000379:methods*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D012160:Retina / Q000378:metabolism
chemical_list: D008024:Ligands; D011956:Receptors, Cell Surface