by Keyword: Photopharmacology

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Gomila, Alexandre M. J., Rustler, Karin, Maleeva, Galyna, Nin-Hill, Alba, Wutz, Daniel, Bautista-Barrufet, Antoni, Rovira, Xavier, Bosch, Miquel, Mukhametova, Elvira, Petukhova, Elena, Ponomareva, Daria, Mukhamedyarov, Marat, Peiretti, Franck, Alfonso-Prieto, Mercedes, Rovira, Carme, König, Burkhard, Bregestovski, Piotr, Gorostiza, Pau, (2020). Photocontrol of endogenous glycine receptors in vivo Cell Chemical Biology 27, (11), 1425-1433.e7

Glycine receptors (GlyRs) are indispensable for maintaining excitatory/inhibitory balance in neuronal circuits that control reflexes and rhythmic motor behaviors. Here we have developed Glyght, a GlyR ligand controlled with light. It is selective over other Cys-loop receptors, is active in vivo, and displays an allosteric mechanism of action. The photomanipulation of glycinergic neurotransmission opens new avenues to understanding inhibitory circuits in intact animals and to developing drug-based phototherapies.

Keywords: Glycine receptors, Photopharmacology, Optopharmacology, Inhibitory neurotransmission, CNS, Photoswitch

Maleeva, Galyna, Nin-Hill, Alba, Rustler, Karin, Petukhova, Elena, Ponomareva, Daria, Mukhametova, Elvira, Gomila-Juaneda, Alexandre, Wutz, Daniel, Alfonso-Prieto, Mercedes, König, Burkhard, Gorostiza, Pau, Bregestovski, Piotr, (2020). Subunit-specific photocontrol of glycine receptors by azobenzene-nitrazepam photoswitcher eneuro 8, (1), 0294-20

Photopharmacology is a unique approach that through a combination of photochemistry methods and advanced life science techniques allows the study and control of specific biological processes, ranging from intracellular pathways to brain circuits. Recently, a first photochromic channel blocker of anion-selective GABAA receptors, Azo-NZ1, has been described. In the present study using patch-clamp technique in heterologous system and in mice brain slices, site-directed mutagenesis and molecular modelling we provide evidence of the interaction of Azo-NZ1 with glycine receptors (GlyRs) and determine the molecular basis of this interaction. Glycinergic synaptic neurotransmission determines an important inhibitory drive in the vertebrate nervous system and plays a crucial role in the control of neuronal circuits in the spinal cord and brain stem. GlyRs are involved in locomotion, pain sensation, breathing and auditory function, as well as in the development of such disorders as hyperekplexia, epilepsy and autism. Here we demonstrate that Azo-NZ1 blocks in a UV dependent manner the activity of alpha2 GlyRs (GlyR2), while being barely active on alpha1 GlyRs (GlyR1). The site of Azo-NZ1 action is in the chloride-selective pore of GlyR at the 2’ position of transmembrane helix 2 and amino acids forming this site determine the difference in Azo-NZ1 blocking activity between GlyR2 and GlyR1. This subunit specific modulation is also shown on motoneurons of brainstem slices from neonatal mice that switch during development from expressing "foetal" GlyR2 to "adult" GlyR1 receptors. Significance Statement Photochromic molecules are becoming widely used for studying and modulating various biological processes. Successful application of these compounds, whose activity can be controlled with light, potentially provides a promising tool for future therapeutic approaches. The main advantage of such compounds is their precise spatial and temporal selectivity, a property that favours specific drug action and diminishes their side effects. In the present study, we describe in detail the interaction of the novel azobenzene-nitrazepam-based photochromic compound (Azo-NZ1) with glycine receptors (GlyRs) and determine its subunit-specific blocking activity in the Cl-selective pore of GlyRs. This compound offers a new strategy for specific control of glycinergic circuits and stepping stone for design of new GlyR-active drugs.

Keywords: Brain slices, Glycine receptors, Hypoglossal motoneurons, Molecular modelling, Patch-clamp, Photopharmacology

Pittolo, Silvia, Lee, Hyojung, Lladó, Anna, Tosi, Sébastien, Bosch, Miquel, Bardia, Lídia, Gómez-Santacana, Xavier, Llebaria, Amadeu, Soriano, Eduardo, Colombelli, Julien, Poskanzer, Kira E., Perea, Gertrudis, Gorostiza, Pau, (2019). Reversible silencing of endogenous receptors in intact brain tissue using two-photon pharmacology Proceedings of the National Academy of Sciences of the United States of America 116, (27), 13680-13689

The physiological activity of proteins is often studied with loss-of-function genetic approaches, but the corresponding phenotypes develop slowly and can be confounding. Photopharmacology allows direct, fast, and reversible control of endogenous protein activity, with spatiotemporal resolution set by the illumination method. Here, we combine a photoswitchable allosteric modulator (alloswitch) and 2-photon excitation using pulsed near-infrared lasers to reversibly silence metabotropic glutamate 5 (mGlu5) receptor activity in intact brain tissue. Endogenous receptors can be photoactivated in neurons and astrocytes with pharmacological selectivity and with an axial resolution between 5 and 10 µm. Thus, 2-photon pharmacology using alloswitch allows investigating mGlu5-dependent processes in wild-type animals, including synaptic formation and plasticity, and signaling pathways from intracellular organelles.

Keywords: Photopharmacology, Photoactivation, Pharmacological selectivity, Functional silencing, 2-photon pharmacology

Matera, Carlo, Gomila-Juaneda, Alexandre, Camarero, Núria, Libergoli, Michela, Soler, Concepció, Gorostiza, Pau, (2018). A photoswitchable antimetabolite for targeted photoactivated chemotherapy Journal of the American Chemical Society 140, (46), 15764-15773

The efficacy and tolerability of systemically administered anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analog of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration, and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small molecules, and a step forward to develop targeted anticancer photochemotherapies with localized efficacy and reduced adverse effects.

Keywords: Photopharmacology, Photodynamic therapy, Antiproliferative, Arthritis, Psoriasis, Nanomedicine