MEDICINAL CHEMISTRY
Group Leader: Amadeu Llebaria
The Medicinal Chemistry group is dedicated to the discovery of small molecules with activity on biologically relevant processes, including medicinal chemistry and chemical biology. The research projects are in the borderline between chemistry and biology with the goal to find molecules useful to study basic processes and mechanisms and to develop new therapeutics for diseases. Main research topics include photopharmacology, immunotherapy and chemical methods for native protein labelling.
web of the group: http://www.iqac.csic.es/mcs
PROJECT LINES
Research activities of the group are focused on drug discovery and chemical biology, aimed at obtaining novel biologically active compounds and their application in new therapies, as well as the development of new pharmacological research tools. Current main lines of research include:
Photopharmacology – Reversible photoswitches
The administration of a photocontrolled ligand in combination with illumination that is patterned in space and time can provide a novel degree of control and regulation of receptor activity. This method would allow focusing the action of the ligand, controlling the location and the temporal extension of its effects. When applied in vivo, the use of photoregulation can reduce side effects by targeting receptors located in specific tissues, establishing personalized drug schedules to patient needs.
In particular, azobenzene photoisomerization can control biological functions. We have obtained phenylazopyridines with light-dependent activity as negative allosteric modulators (NAM) of metabotropic glutamate receptor subtype 5 (mGlu5), that result in atypical pharmacological profiles, both in vitro and in vivo, in studies of zebrafish larva motility and the regulation of the antinociceptive effects in mice. Thus, local administration of a photoswitchable compound combined with irradiation with light in the peripheral tissues of rodents or in the brain results in a precise illumination-dependent analgesic effect.
Also, azobenzene photoswitchable allosteric modulators of mGlu4 allow the control of endogenous receptor with light and reversible inhibition of persistent pain symptoms by receptor photocontrol in specific positions in the brain of freely behaving animals.
These compounds can be used to define novel and more precise therapeutic treatments and to study in vivo the physiological roles of the receptors.
Photopharmacology – Photolabile caged compounds
Another approach to control the activity of therapeutic compounds by means of light is through the use of photolabile compounds. These are caged drugs, inactive while caged, that result in the controlled release of the active compound when irradiated with light.
JF-NP-26 is a coumarin-caged derivative of raseglurant, an mGlu5 receptor negative allosteric modulator. Light illumination of JF-NP-26 induces a photochemical reaction releasing the active drug, which effectively controls mGlu5 receptor activity both in ectopic expressing systems and in striatal primary neurons.
After systemic administration of JF-NP-26 in mice, local light-emitting diode (LED)-based illumination, either of the thalamus or the peripheral tissues, induces light-dependent analgesia both in neuropathic and in acute/tonic inflammatory pain models.
This is the first example of photocontrol of analgesia in vivo using a caged mGlu5 receptor negative allosteric modulator.
Immunotherapy – Non-glycosidic analogues of α-GalCer as NKT cell activators
NKT cells, a unique subpopulation of T cells with immunomodulatory properties involved in a broad range of immune responses, are stimulated by glycolipid antigens, particularly by alpha-galactosylceramide (α-GalCer).
α-GalCer shows an exceptional potency on NKT cell stimulation which is associated to different side effects. In addition, it simultaneously induces the expression of both Th1 and Th2 cytokines, which have opposite biological functions. For this reason, new compounds are being developed that allow a selective modulation of cytokine production.
In our group we have developed a new family of non-glycosidic analogues of α-GalCer that show strong activity in vitro to stimulate NKT cell proliferation and highly efficient and potent selective cytokine release.
These compounds can have application in cancer immunotherapy, for cooperative stimulation of the patient immune system, and as vaccine adjuvants in autoimmune diseases or infections.
Selective protein labelling
We have developed a protein labelling method that consists in the selective and kinetically controlled conjugation on lysine residues exposed on the surface of the protein near the binding site of the ligand.
This approach is based on bioortogonal click-chemical reactions, in which a fast triazole synthesis from chemically stable azide and alkyne components results in an N- or S- diversely substituted imino or thiosugar ligand library. The protein affinity of the sugar-like ligand with a short lived NHS-ester group directs the chemical reaction on a terminal amino group of a specific lysine in the native protein.
This results in a practical chemical method for the selective covalent labelling of wild type proteins with high affinity without requiring previous genetic or chemical modification of the protein. Its modularity allows the application to multiple proteins and ligands.
Scientific staff
Amadeu Llebaria
Scientific Researcher
amadeu.llebaria@iqac.csic.es
Lab people
Carme Serra
Contracted Researcher
carme.serra@iqac.csic.es
Juan Lorenzo Catena
Contracted Researcher
juanlo.catena@iqac.csic.es
Silvia Panarello
Contracted Researcher
silvia.panarello@iqac.csic.es
Xavier Rovira
Ramon y Cajal Researcher
xavier.rovira@iqac.csic.es
Lourdes Muñoz
Specialist Technician
lourdes.munoz@iqac.csic.es
Laia Josa Culleré
Postdoctoral Researcher Marie Sklodowska-Curie
laia.josacullere@iqac.csic.es
Elisabet Perez
Postdoctoral Researcher
Gloria Somalo
Predoctoral Researcher
gloria.somalo@iqac.csic.es
Anna Duran
Predoctoral Researcher
anna.duran@iqac.csic.es
Anaëlle Dumazer
Predoctoral Researcher
anaelle.dumazer@iqac.csic.es
Aleix González
Predoctoral Researcher
aleix.gonzalez@iqac.csic.es
Teresa Sarrias
Technician
teresa.sarrias@iqac.csic.es
Xavier Gómez
Tecniospring Industry-Marie Skłodowska-Curie Researcher
xavier.gomez@iqac.csic.es
- Conformational diversity in class C GPCR positive allosteric modulation-
Cannone, Giuseppe, Berto, Ludovic, Malhaire, Fanny, Ferguson, Gavin, Fouillen, Aurelien, Balor, Stéphanie, Font-Ingles, Joan, Llebaria, Amadeu, Goudet, Cyril, Kotecha, Abhay, K R, Vinothkumar, Lebon, Guillaume
Nature communications, 16(1), pp. 619 2025 - Hemithioindigo-based histone deacetylase inhibitors induce a light-dependent anticancer effect-
Laia Josa-Culleré, Carla Aira Rodríguez, Amadeu Llebaria
European Journal of Medicinal Chemistry,Volume 279, 116846 - A 'double-edged' role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs-
Serena NotartomasoNico AntenucciMariacristina MazzitelliXavier RoviraSerena BoccellaFlavia RicciardiFrancesca LiberatoreXavier Gomez-SantacanaTiziana ImbriglioMilena CannellaCharleine ZussyLivio LuongoSabatino MaioneCyril GoudetGiuseppe BattagliaAmadeu LlebariaFerdinando Nicoletti Is a corresponding author Volker Neugebauer
eLife 13:e94931, 2024 - Photoswitchable positive allosteric modulators of metabotropic glutamate receptor 4 to improve selectivity-
Silvia Panarello, Aleix González-Díez, Alice E. Berizzi, Fanny Malhaire, Roser Borràs-Tudurí, Xavier Rovira, Carme Serra, Laurent Prézeau, Jean-Philippe Pin, Cyril Goudet, Amadeu Llebaria, Xavier Gómez-Santacana
iScience 27, 110123 - Boosting the Impact of EFMC Young Scientists Network Through the Creation of Working Groups-
Mari, M., Lanthier, C., Proj, M., Donckele, E.J., Josa-Culleré, L., Goncharenko, K., Leroy, S., Matagne, B., McKenna, S.M., Borsari, C.
ChemMedChem, 2024.
- Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite-
Hu, H., Serra, C., Zhang, W., Scrivo, A., Fernández-Carasa, I., Consiglio, A., Aytes, A., Pujana, M.A., Llebaria, A., Antolin, A.A.
Cell Chemical Biology, 2024
- Optical Control of Adenosine A2A Receptor Using Istradefylline Photosensitivity-
Dumazer, A., Gómez-Santacana, X., Malhaire, F., Jopling, C., Maurel, D., Lebon, G., Llebaria, A., Goudet, C.
ACS Chemical Neuroscience 2024 15 (3), 645-655
- Design and validation of a low-cost photomodulator for in vivo photoactivation of a mGluR5 inhibitor-
Ajieren, H., Fox, A., Biggs, E., Albors, G., Llebaria, A., Irazoqui, P.
Biomedical Engineering Letters, 14 (2), pp. 245-254. 2024.
- Mitochondria-targeted melatonin photorelease supports the presence of melatonin MT1 receptors in mitochondria inhibiting respiration-
Somalo-Barranco, G., Pagano Zottola, A.C., Abdulrahman, A.O., El Zein, R.M., Cannich, A., Muñoz, L., Serra, C., Oishi, A., Marsicano, G., Masri, B., Bellocchio, L., Llebaria, A., Jockers, R.
Cell Chemical Biology, 30 (8), pp. 920-932.e7. 2023
- The antioxidant l-Ergothioneine prevents cystine lithiasis in the Slc7a9−/− mouse model of cystinuria-
Clara Mayayo-Vallverdú, Miguel López de Heredia, Esther Prat, Laura González, Meritxell Espino Guarch, Clara Vilches, Lourdes Muñoz, Miguel A. Asensi, Carmen Serra, Amadeu Llebaria, Mercedes Casado, Rafael Artuch, Gloria Garrabou, Pablo M. Garcia-Roves, Federico V. Pallardó, Virginia Nunes
Redox Biology (2023)
- Total synthesis of C37 alken-2-one temperature geomarkers-
Anna Alcaide, Carme Serra, Juanlo Catena, Lourdes Muñoz, Amadeu Llebaria
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2023.154571
- A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia-
José M. Carbó, Josep M. Cornet-Masana, Laia Cuesta-Casanovas, Jennifer Delgado-Martínez, Antònia Banús-Mulet, Lise Clément-Demange, Carme Serra, Juanlo Catena, Amadeu Llebaria, Jordi Esteve and Ruth M. Risueño
Cancers 2023, 15(6), 1912
- Visible-Light-Controlled Histone Deacetylase Inhibitors for Targeted Cancer Therapy-
Josa-Culleré, L., Llebaria, A.
Journal of Medicinal Chemistry, 66 (3), pp. 1909-1927. 2023
- Photopharmacological manipulation of amygdala metabotropic glutamate receptor mGlu4 alleviates neuropathic pain-
Vanessa Pereira, Juri Aparicio Arias, Amadeu Llebaria, Cyril Goudet
Pharmacological Research 187 (2023) 106602
- Caged-carvedilol as a new tool for visible-light photopharmacology of β-adrenoceptors in native tissues-
Duran-Corbera, A., Font, J., Faria, M., Prats, E., Consegal, M., Catena, J., Muñoz, L., Raldua, D., Rodriguez-Sinovas, A., Llebaria, A., Rovira, X.
iScience, 25 (10), art. no. 105128, 2022
- Photoswitchable allosteric modulators for metabotropic glutamate receptors-
Xavier Gómez-Santacana, Silvia Panarello, Xavier Rovira, Amadeu Llebaria
Current Opinion in Pharmacology, Volume 66, 102266, October 2022
- Light-Induced Activation of a Specific Type-5 Metabotropic Glutamate Receptor Antagonist in the Ventrobasal Thalamus Causes Analgesia in a Mouse Model of Breakthrough Cancer Pain-
Notartomaso, S., Antenucci, N., Liberatore, F., Mascio, G., Boccadamo Pompili, S.V., Font, J., Scioli, M., Luongo, L., Arcella, A., Gradini, R., Llebaria, A., Nicoletti, F.
International journal of molecular sciences, 23 (14), 2022
- A Photoswitchable Ligand Targeting the β1-Adrenoceptor Enables Light-Control of the Cardiac Rhythm-
Duran-Corbera, A., Faria, M., Ma, Y., Prats, E., Dias, A., Catena, J., Martinez, K.L., Raldua, D., Llebaria, A., Rovira, X.
Angewandte Chemie - International Edition, 2022
- Fast Photoswitchable Molecular Prosthetics Control Neuronal Activity in the Cochlea-
Garrido-Charles, A., Huet, A., Matera, C., Thirumalai, A., Hernando, J., Llebaria, A., Moser, T., Gorostiza, P.
Journal of the American Chemical Society, 144 (21), pp. 9229-9239. 2022
- Environmental levels of carbaryl impair zebrafish larvae behaviour: The potential role of ADRA2B and HTR2B-
Faria, M., Bellot, M., Bedrossiantz, J., Ramírez, J.R.R., Prats, E., Garcia-Reyero, N., Gomez-Canela, C., Mestres, J., Rovira, X., Barata, C., Oliván, L.M.G., Llebaria, A., Raldua, D.
Journal of Hazardous Materials, 431, art. no. 128563, 2022
- Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface-
Liu, L., Fan, Z., Rovira, X., Xue, L., Roux, S., Brabet, I., Xin, M., Pin, J.-P., Rondard, P., Liu, J.
eLife, 10, art. no. e70188, 2021.
- S-Methyl-L-Ergothioneine to L-Ergothioneine Ratio in Urine Is a Marker of Cystine Lithiasis in a Cystinuria Mouse Model-
de Heredia, M.L., Muñoz, L., Carru, C., Sotgia, S., Zinellu, A., Serra, C., Llebaria, A., Kato, Y., Nunes, V.
Antioxidants, 10 (9), art. no. 1424, . 2021
- Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations-
Nasrallah, C., Cannone, G., Briot, J., Rottier, K., Berizzi, A.E., Huang, C.-Y., Quast, R.B., Hoh, F., Banères, J.-L., Malhaire, F., Berto, L., Dumazer, A., Font-Ingles, J., Gómez-Santacana, X., Catena, J., Kniazeff, J., Goudet, C., Llebaria, A., Pin, J.-P., Vinothkumar, K.R., Lebon, G.
Cell Reports, 36 (9), art. no. 109648, . 2021
- Remote local photoactivation of morphine produces analgesia without opioid-related adverse effects-
López-Cano, M., Font, J., Aso, E., Sahlholm, K., Cabré, G., Giraldo, J., De Koninck, Y., Hernando, J., Llebaria, A., Fernández-Dueñas, V., Ciruela, F.
British Journal of Pharmacology, 180 (7), pp. 958-974. 2021.
- New Paradigm in NKT Cell Antigens: MCS-0208 (2-(Hydroxymethyl)phenylthio-phytoceramide) – an Aryl-Phytoceramide Compound with a Single Hydroxyl Group Stimulates NKT Cells-
Borràs-Tudurí, R., Alcaide, A., Aspeslag, S., Usero, L., Serra, C., Roura-Mir, C., Elewaut, D. and Llebaria, A.
ChemMedChem. 16 (16), pp. 2491-2496. 2021
- In the Search for Photocages Cleavable with Visible Light: An Overview of Recent Advances and Chemical Strategies-
Josa-Culleré, L., Llebaria, A.
ChemPhotoChem, 5, 4, 298-316, 2021 - Mimetics of extra virgin olive oil phenols with anti-cancer stem cell activity-
Cuyàs, E., Gumuzio, J., Lozano-Sánchez, J., Segura-Carretero, A., Verdura, S., Bosch-Barrera, J., Martin-Castillo, B., Nonell-Canals, A., Llebaria, A., Cabello, S., Serra, C., Sanchez-Martinez, M., Martin, ÁG., Menendez, J.A.
Aging, 12 (21), pp. 21057-21075. 2020
- Mechanistic Insights into Light-Driven Allosteric Control of GPCR Biological Activity-
Ricart-Ortega, M., Berizzi, A.E., Pereira, V., Malhaire, F., Catena, J., Font, J., Gómez-Santacana, X., Munõz, L., Zussy, C., Serra, C., Rovira, X., Goudet, C., Llebaria, A.
ACS Pharmacology and Translational Science, 3 (5), pp. 883-895. 2020
- Development and validation of a mass spectrometry binding assay for mGlu5 receptor-
Ricart-Ortega, M., Berizzi, A.E., Catena, J., Malhaire, F., Muñoz, L., Serra, C., Lebon, G., Goudet, C., Llebaria, A.
Analytical and bioanalytical chemistry 2020
- Photoswitchable Antagonists for a Precise Spatiotemporal Control of β2-Adrenoceptors-
Duran-Corbera, A., Catena, J., Otero-Viñas, M., Llebaria, A., Rovira, X.
Journal of medicinal chemistry, 63 (15), pp. 8458-8470. 2020
- Reversible silencing of endogenous receptors in intact brain tissue using 2-photon pharmacology-
Silvia Pittolo, Hyojung Lee, Anna Lladó, Sébastien Tosi, Miquel Bosch, Lídia Bardia, Xavier Gómez-Santacana, Amadeu Llebaria, Eduardo Soriano, Julien Colombelli, Kira E. Poskanzer, Gertrudis Perea, and Pau Gorostiza
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1900430116
- Optical Modulation of Metabotropic Glutamate Receptor Type 5 In Vivo Using a Photoactive Drug-
Marc López-Cano, Joan Font, Amadeu Llebaria, Víctor Fernández-Dueñas, Francisco Ciruela
Methods in Molecular BiologyVolume 1947, 2019, Pages 351-359
- GPCR photopharmacology-
Ricart-Ortega, M., Font, J., Llebaria, A.
Molecular and Cellular Endocrinology, 488, pp. 36-51.2019
- A light-controlled allosteric modulator unveils a role for mGlu4 receptors during early stages of ischemia in the rodent cerebellar cortex-
Bossi S, Helleringer R, Galante M, Monlleó E, Trapero A, Rovira X, Daniel H, Llebaria A, McLean H
Front. Cell. Neurosci., 2018, 12, 449
- Dietary and microbial oxazoles induce intestinal inflammation by modulating aryl hydrocarbon receptor responses.-
Shankar S. Iyer, Thomas Gensollen, Amit Gandhi, Sungwhan F. Oh, Joanna F. Neves, Frederic Collin, Richard Lavin, Carme Serra, Jonathan Glickman, Punyanganie S. A. de Silva, R. Balfour Sartor, Gurdyal Besra, Russell Hauser, , Anthony Maxwell, Amadeu Llebaria, Richard S. Blumberg
Cell, 2018, 173(5), 1125-1134.e11
- Dynamic modulation of inflammatory pain-related affective and sensory symptoms by optical control of amygdala metabotropic glutamate receptor 4-
Zussy C, Gómez-Santacana X, Rovira X, De-Bundel D, Ferrazzo S, Bosch D, Asede D, Malhaire F, Acher F, Giraldo J, Valjent E, Ehrlich I, Ferraguti F, Pin J-P, Llebaria A, Goudet C
Mol Psychiatry. 2018, 23(3): 509-520.
- Optical activation of endogenous metabotropic glutamate receptor 4 (mGlu4) in the amygdala dynamically regulates symptoms associated with persistent inflammatory pain-
Zussy C, Gómez-Santacana X, Rovira X, de Bundel D, Ferrazzo S, Bosch D, Asede D, Malhaire F, Acher F, Giraldo J, Valjent E, Ehrlich I, Ferraguti F, Pin JP, Llebaria A, Goudet C
Mol. Psychiatr. 2018, 23(3): 489.
- Direct coupling of detergent purified human mGlu5 receptor to the heterotrimeric G proteins Gq and Gs-
Nasrallah C, Rottier K, Marcellin R, Compan V, Font J, Llebaria A, Pin JP, Banères JL, Lebon G
Sci. Rep. 2018, 8(1), 4407.
- Shedding light on metabotropic glutamate receptors using optogenetics and photopharmacology-
Goudet C, Rovira X, Llebaria A
Curr. Opin. Pharmacol. 2018; 38: 8-15.
- Mechanical allodynia assessment in a murine neuropathic pain model-
Notartomaso S, Scarselli P, Di Pietro P, Battaglia G, Llebaria A, Ciruela F, Nicoletti F
Bio-protocol. 2018, 8(2), e2671.
- Allosteric control of an asymmetric transduction in a G protein-coupled receptor heterodimer-
Liu J, Zhang Z, Moreno-Delgado D, Dalton JA, Rovira X, Trapero A, Goudet C, Llebaria A, Giraldo J, Yuan Q, Rondard P, Huang S, Liu J, Pin JP
eLife. 2017; 6. e26985.
- Formalin murine model of pain-
López-Cano M, Fernández-Dueñas V, Llebaria A, Ciruela F
Bio-protocol. 2017, 7(23), e2628.
- Optical control of pain in vivo with a photoactive mGlu(5) receptor negative allosteric modulator-
Font J, López-Cano M, Notartomaso S, Scarselli P, Di Pietro P, Bresolí-Obach R, Battaglia G, Malhaire F, Rovira X, Catena J, Giraldo J, Pin JP, Fernández-Dueñas V, Goudet C, Nonell S, Nicoletti F, Llebaria A, Ciruela F
eLife. 2017; 6. e23545.
- Illuminating Phenylazopyridines To Photoswitch Metabotropic Glutamate Receptors: From the Flask to the Animals-
Gómez-Santacana X, Pittolo S, Rovira X, Lopez M, Zussy C, Dalton JAR, Faucherre A, Jopling C, Pin JP, Ciruela F, Goudet C, Giraldo J, Gorostiza P, Llebaria A
ACS Cent. Sci., 2017, 3 (1), pp 81–91.
- OptoGluNAM4.1, a Photoswitchable Allosteric Antagonist for Real-Time Control of mGlu4 Receptor Activity.-
Rovira X, Trapero A, Pittolo S, Zussy C, Faucherre A, Jopling C, Giraldo J, Pin JP, Gorostiza P, Goudet C, Llebaria A.
Cell Chem Biol. 2016 Aug 18;23(8):929-34
- Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches.-
Izquierdo-Serra M, Bautista-Barrufet A, Trapero A, Garrido-Charles A, Díaz-Tahoces A, Camarero N, Pittolo S, Valbuena S, Pérez-Jiménez A, Gay M, García-Moll A, Rodríguez-Escrich C, Lerma J, de la Villa P, Fernández E, Pericàs MÀ, Llebaria A, Gorostiza P.
Nat Commun. 2016 Jul 20;7:12221.
- Shining Light on an mGlu5 Photoswitchable NAM: A Theoretical Perspective.-
Dalton JA, Lans I, Rovira X, Malhaire F, Gómez-Santacana X, Pittolo S, Gorostiza P, Llebaria A, Goudet C, Pin JP, Giraldo J.
Curr Neuropharmacol. 2016;14(5):441-54;
- High precision cardioprotective therapy: a photoswitchable approach to reduce the extension of myocardial infarction-
Coordinator: Amadeu Llebaria Soldevila
Grant: LCF/PR/HR21/52410029, "LaCaixa" Foundation through Caixa Research Health award
Period: 10/2021-10/2024
- Nuevas estrategias en fotofarmacología de receptores GPCR-
Coordinator: Amadeu Llebaria Soldevila
Grant: PID2020-120499RB-I00 funded by MCIN/ AEI/10.13039/501100011033
Period: 2021-2024
Funding: 157.320,00
- Mecanismos neuromoduladores sinápticos de la amígdala y el papel de mGlu4 en los trastornos del espectro autista.-
Coordinator: Amadeu Llebaria Soldevila
Grant: PCI2018-093047 funded by MCIN/ AEI/10.13039/501100011033
Period: 2018-2022
Funding: 150.000,00
- Adquisición de un purificador híbrido flash/HPLC con detectores de UV-MS-ELS en el Instituto de Química Avanzada de Cataluña.-
Coordinator: Amadeu Llebaria Soldevila
Grant: EQC2019-005875-P funded by Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación and European Union European Regional Development Fund
Period: 2019-2022
Funding: 214.219,91
