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30 results on '"Laurent Le Corre"'

1. Implication of the LRR Domain in the Regulation and Activation of the NLRP3 Inflammasome

Author

Margaux Cescato, Yixiang Y J Zhu, Laurent Le Corre, Bénédicte F Py, Sophie Georgin-Lavialle, and Mathieu P Rodero

Subjects
inflammasome, NLRP3, Leucine-Rich Repeat domain, LRR, CAPS, Cytology, QH573-671
Abstract

The NLRP3 inflammasome is a critical component of the innate immune response. NLRP3 activation is a tightly controlled process involving an initial priming to express NLRP3, pro-IL-1 β, and pro-IL-18, followed by an activation signal. The precise mechanism of activation is not fully understood due to the diverse range of activators, yet it effectively orchestrates the activation of caspase-1, which subsequently triggers the release of proinflammatory cytokines IL-1β and IL-18. NLRP3 dysregulation can lead to a variety of inflammatory diseases, highlighting its significant role in immune response and disease pathogenesis. NLRP3 is divided into three domains: the PYD, the NACHT, and the LRR domains. This review focuses on the LRR domain of NLRP3, detailing its structural characteristics, its function in pathogen sensing, its role in the degradation process, and its involvement in inflammasome auto-inhibition and activation. Additionally, we discuss the impact of mutations within the LRR domain found in atypical Cryopyrin-Associated Periodic Syndromes (CAPS), highlighting the clinical relevance of this domain.

Published
2024
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2. Mechanism-based and computational modeling of hydrogen sulfide biogenesis inhibition: interfacial inhibition

Author

Laurent Le Corre and Dominique Padovani

Subjects
Medicine, Science
Abstract

Abstract Hydrogen sulfide (H2S) is a gaseous signaling molecule that participates in various signaling functions in health and diseases. The tetrameric cystathionine γ-lyase (CSE) contributes to H2S biogenesis and several investigations provide evidence on the pharmacological modulation of CSE as a potential target for the treatment of a multitude of conditions. D-penicillamine (D-pen) has recently been reported to selectively impede CSE-catalyzed H2S production but the molecular bases for such inhibitory effect have not been investigated. In this study, we report that D-pen follows a mixed-inhibition mechanism to inhibit both cystathionine (CST) cleavage and H2S biogenesis by human CSE. To decipher the molecular mechanisms underlying such a mixed inhibition, we performed docking and molecular dynamics (MD) simulations. Interestingly, MD analysis of CST binding reveals a likely active site configuration prior to gem-diamine intermediate formation, particularly H-bond formation between the amino group of the substrate and the O3′ of PLP. Similar analyses realized with both CST and D-pen identified three potent interfacial ligand-binding sites for D-pen and offered a rational for D-pen effect. Thus, inhibitor binding not only induces the creation of an entirely new interacting network at the vicinity of the interface between enzyme subunits, but it also exerts long range effects by propagating to the active site. Overall, our study paves the way for the design of new allosteric interfacial inhibitory compounds that will specifically modulate H2S biogenesis by cystathionine γ-lyase.

Published
2023
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3. Persulfidation of DJ-1: Mechanism and Consequences

Author

Erwan Galardon, Nicolas Mathas, Dominique Padovani, Laurent Le Corre, Gabrielle Poncet, and Julien Dairou

Subjects
persulfide, DJ-1, hydrogen sulfide, sulfinic, Microbiology, QR1-502
Abstract

DJ-1 (also called PARK7) is a ubiquitously expressed protein involved in the etiology of Parkinson disease and cancers. At least one of its three cysteine residues is functionally essential, and its oxidation state determines the specific function of the enzyme. DJ-1 was recently reported to be persulfidated in mammalian cell lines, but the implications of this post-translational modification have not yet been analyzed. Here, we report that recombinant DJ-1 is reversibly persulfidated at cysteine 106 by reaction with various sulfane donors and subsequently inhibited. Strikingly, this reaction is orders of magnitude faster than C106 oxidation by H2O2, and persulfidated DJ-1 behaves differently than sulfinylated DJ-1. Both these PTMs most likely play a dedicated role in DJ-1 signaling or protective pathways.

Published
2022
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4. New MraYAA Inhibitors with an Aminoribosyl Uridine Structure and an Oxadiazole

Author

Hongwei Wan, Raja Ben Othman, Laurent Le Corre, Mélanie Poinsot, Martin Oliver, Ana Amoroso, Bernard Joris, Thierry Touzé, Rodolphe Auger, Sandrine Calvet-Vitale, Michaël Bosco, and Christine Gravier-Pelletier

Subjects
MraY transferase, inhibitors synthesis, muraymycin analogs, molecular modeling, inhibition tests, Therapeutics. Pharmacology, RM1-950
Abstract

New inhibitors of the bacterial transferase MraY from Aquifex aeolicus (MraYAA), based on the aminoribosyl uridine central core of known natural MraY inhibitors, have been designed to generate interaction of their oxadiazole linker with the key amino acids (H324 or H325) of the enzyme active site, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin. A panel of ten compounds was synthetized notably thanks to a robust microwave-activated one-step sequence for the synthesis of the oxadiazole ring that involved the O-acylation of an amidoxime and subsequent cyclization. The synthetized compounds, with various hydrophobic substituents on the oxadiazole ring, were tested against the MraYAA transferase activity. Although with poor antibacterial activity, nine out of the ten compounds revealed the inhibition of the MraYAA activity in the range of 0.8 µM to 27.5 µM.

Published
2022
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5. Structure of the essential peptidoglycan amidotransferase MurT/GatD complex from Streptococcus pneumoniae

Author

Cécile Morlot, Daniel Straume, Katharina Peters, Olav A. Hegnar, Nolwenn Simon, Anne-Marie Villard, Carlos Contreras-Martel, Francisco Leisico, Eefjan Breukink, Christine Gravier-Pelletier, Laurent Le Corre, Waldemar Vollmer, Nicolas Pietrancosta, Leiv Sigve Håvarstein, and André Zapun

Subjects
Science
Abstract

The amidotransferase MurT/GatD complex catalyzes peptidoglycan precursor amidation in some Gram-positive bacteria. Here the authors present the crystal structure of the Streptococcus pneumoniae MurT/GatD complex and provide mechanistic insights, which are of interest for drug development.

Published
2018
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6. A Sub-Micromolar MraYAA Inhibitor with an Aminoribosyl Uridine Structure and a (S,S)-Tartaric Diamide: Synthesis, Biological Evaluation and Molecular Modeling

Author

Martin Oliver, Laurent Le Corre, Mélanie Poinsot, Michaël Bosco, Hongwei Wan, Ana Amoroso, Bernard Joris, Ahmed Bouhss, Sandrine Calvet-Vitale, and Christine Gravier-Pelletier

Subjects
MraY transferase, inhibitors synthesis, carbacaprazamycin analogs, molecular docking studies, inhibition tests, Organic chemistry, QD241-441
Abstract

New inhibitors of the bacterial tranferase MraY are described. Their structure is based on an aminoribosyl uridine scaffold, which is known to be important for the biological activity of natural MraY inhibitors. A decyl alkyl chain was introduced onto this scaffold through various linkers. The synthesized compounds were tested against the MraYAA transferase activity, and the most active compound with an original (S,S)-tartaric diamide linker inhibits MraY activity with an IC50 equal to 0.37 µM. Their antibacterial activity was also evaluated on a panel of Gram-positive and Gram-negative strains; however, the compounds showed no antibacterial activity. Docking and molecular dynamics studies revealed that this new linker established two stabilizing key interactions with N190 and H325, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin.

Published
2022
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7. Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5’-alkynylation

Author

Raja Ben Othman, Mickaël J. Fer, Laurent Le Corre, Sandrine Calvet-Vitale, and Christine Gravier-Pelletier

Subjects
diastereoselective alkynylation, nucleoside, protecting groups, uridine, Science, Organic chemistry, QD241-441
Abstract

The 5’-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2’,3’-di-O-protecting groups (R1): O-alkyl groups led to modest diastereoselectivities (65:35) in favor of the 5’R-isomer, whereas O-silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5’S-isomer. A study related to this protecting group effect on the diastereoselectivity is reported.

Published
2017
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10. Human Orphan Cytochrome P450 2U1 Catalyzes the ω-Hydroxylation of Leukotriene B

Author

Khawla, Nouri, Nicolas, Pietrancosta, Laurent, Le Corre, Patrick M, Dansette, Daniel, Mansuy, and Jean-Luc, Boucher

Subjects
Cytochrome P-450 Enzyme System, Fatty Acids, Humans, Hydroxylation, Cytochrome P450 Family 2, Leukotriene B4
Abstract

Cytochrome P450 2U1 (CYP2U1) identified from the human genome remains poorly known since few data are presently available on its physiological function(s) and substrate(s) specificity. CYP2U1 mutations are associated with complicated forms of hereditary spastic paraplegia, alterations of mitochondrial architecture and bioenergetics. In order to better know the biological roles of CYP2U1, we used a bioinformatics approach. The analysis of the data invited us to focus on leukotriene B

Published
2022

11. New MraY

Author

Hongwei, Wan, Raja, Ben Othman, Laurent, Le Corre, Mélanie, Poinsot, Martin, Oliver, Ana, Amoroso, Bernard, Joris, Thierry, Touzé, Rodolphe, Auger, Sandrine, Calvet-Vitale, Michaël, Bosco, and Christine, Gravier-Pelletier

Abstract

New inhibitors of the bacterial transferase MraY from

Published
2022

12. Implication of folate deficiency in CYP2U1 loss of function

Author

Livia Parodi, Khalid Hamid El Hachimi, Stéphane Zuily, Marine Legendre, Diana Rodriguez, Dario Saracino, Aleksandra Trifunovic, Silvina Perin, Nicolas Villain, Marijana Croon, Thierry Kuntzer, Mahmoud Y. Issa, Fanny Mochel, Filippo M. Santorelli, Foudil Lamari, Priscilla Thomas, Cyril Goizet, Chantal Tse, Claire Ewenczyk, Florence Fellmann, Maha S. Zaki, Arnaud Mourier, Patrick Giavalisco, Laurent Le Corre, Aurélien Trimouille, Emilie Blond, Milica Popovic, Frédéric Darios, Anastasia D. Gazi, Cyril Mignot, Isabelle Kemlin, Sophie M. Steculorum, Cécilia Marelli-Tosi, Joseph G. Gleeson, Mathilde Renaud, Claire Pujol, Jean-Luc Boucher, S. Mathieu, Shahira Elshafie, Anne Legrand, Serge Picaud, Alexandra Durr, Giulia Coarelli, Giovanni Stevanin, Manon Valet, Daniele Galatolo, Rana Alkouri, Alexandre Seyer, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Biologie mitochondriale – Mitochondrial biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Universität zu Köln, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université (SU), Fayoum University, National Research Centre - NRC (EGYPT), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), CHU Bordeaux [Bordeaux], Université de Bordeaux (UB), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, University of California [San Diego] (UC San Diego), University of California, Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université de Lausanne (UNIL), Hospices Civils de Lyon (HCL), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Profilomic [Boulogne-Billancourt], Max planck Institute for Biology of Ageing [Cologne], Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute for Metabolism Research [Cologne, Allemagne], Max-Planck-Gesellschaft, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Core is supported by 'Investissements d’avenir' (ANR-10-IAIHU-06 and ANR-11-INBS-0011-NeurATRIS) and the 'Fondation pour la Recherche Medicale. This study was supported financially by the Association Strümpell-Lorrain–Hereditary Spastic Paraplegia patient association (to C. Pujol and G. Stevanin), the Tom Wahlig–Stiftung Foundation (to K.H. El Hachimi and G. Stevanin), the EMBO short-term fellowship (C. Pujol), French state funds through the Agence Nationale de la Recherche under the framework programme Investissements d’Avenir (ANR-10-INBS-07 PHENOMIN), and the European Union through an internal call under the Seventh Framework Programme (NEUROMICS, to G. Stevanin)., ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), European Project: 305121,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,NEUROMICS(2012), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Universität zu Köln = University of Cologne, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Trousseau [APHP], University of California (UC), Université de Lausanne = University of Lausanne (UNIL), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Lemesle, Marie, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, Infrastructures - INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS - - PHENOMIN2010 - ANR-10-INBS-0007 - INBS - VALID, Integrated European –omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases - NEUROMICS - - EC:FP7:HEALTH2012-10-01 - 2017-09-30 - 305121 - VALID, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Proteomics, Immunology, Mitochondrion, Biology, Folic Acid Deficiency, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Folic Acid, Immunology and Allergy, Animals, Humans, Cytochrome P450 Family 2, Gene, Loss function, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Neopterin, Brain, Phenotype, 3. Good health, Mitochondria, Mice, Inbred C57BL, Disease Models, Animal, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Coenzyme Q – cytochrome c reductase, Mutation, Cancer research, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, CYP2U1, 030217 neurology & neurosurgery, Function (biology), Biomarkers
Abstract

International audience; Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenicmechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, lossof which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomicstudies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels asputative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We alsoconfirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disruptsmitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in ourmouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.

Published
2021
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13. A Promising Approach for Controlling the Second Coordination Sphere of Biomimetic Metal Complexes: Encapsulation in a Dynamic Hydrogen-Bonded Capsule

Author

Olivia Reinaud, Laurent Le Corre, Benoit Colasson, Tongtong Zhang, Université de Paris (UP), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Anions, Coordination sphere, Hydrogen, chemistry.chemical_element, Nanotechnology, 010402 general chemistry, 01 natural sciences, Catalysis, Metal, Deprotonation, Biomimetic Materials, Coordination Complexes, Molecule, [CHIM.COOR]Chemical Sciences/Coordination chemistry, ComputingMilieux_MISCELLANEOUS, 010405 organic chemistry, Chemistry, Organic Chemistry, Cationic polymerization, Hydrogen Bonding, General Chemistry, 0104 chemical sciences, Encapsulation (networking), Solvent, visual_art, visual_art.visual_art_medium
Abstract

The design of biomimetic models of metalloenzymes needs to take into account many factors and is therefore a challenging task. We propose in this work an original strategy to control the second coordination sphere of a metal centre and its distal environment. A biomimetic complex, reproducing the first coordination sphere, is encapsulated in a self-assembled hydrogen-bonded capsule. The cationic complex is co-encapsulated with its counter-anion or with solvent molecules. The capsule is dynamic, allowing a fast in/out exchange of the co-encapsulated species. It also provides both a hydrogen-bonding site in the second coordination sphere and a source of proton as it can be deprotonated in the presence of the complex, providing a globally neutral host-guest assembly. This simple and broad scope strategy is unprecedented in biomimetic studies. The approach appears to be a very promising method for the stabilisation of reactive species and for the study of their reactivity.

Published
2020
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14. Discovery, SAR study and ADME properties of methyl 4-amino-3-cyano-1-(2-benzyloxyphenyl)-1

Author

Jeanne, Fichez, Cathia, Soulie, Laurent, Le Corre, Sophie, Sayon, Stéphane, Priet, Karine, Alvarez, Olivier, Delelis, Patrick, Gizzi, Guillaume, Prestat, Christine, Gravier-Pelletier, Anne-Geneviève, Marcelin, Vincent, Calvez, and Patricia, Busca

Subjects
Chemistry
Abstract

Inspired by the antiviral activity of known pyrazole-based HIV inhibitors, we screened our in-house library of pyrazole-based compounds to evaluate their in cellulo activity against HIV-1 replication. Two hits with very similar structures appeared from single and multiple-round infection assays to be non-toxic and active in a dose-dependent manner. Chemical expansion of their series allowed an in-depth and consistent structure–activity-relationship study (SAR) to be built. Further ADME evaluation led to the selection of 4-amino-3-cyano-1-(2-benzyloxyphenyl)-1H-pyrazole-5-carboxylate with an advantageous pharmacokinetic profile. Finally, examination of its mode of action revealed that this compound does not belong to the three main classes of anti-HIV drugs, a feature of prime interest in the context of viral resistance.

Published
2020

15. Synthesis of Multifunctionalized 2-Iminothiazolidin-4-ones and Their 2-Arylimino Derivatives

Author

Christine Gravier-Pelletier, Laurent Le Corre, Christiane Garbay, Emmanuelle Braud, Maria Chiara Dasso Lang, Mélanie Etheve-Quelquejeu, and Patricia Busca

Subjects
010405 organic chemistry, Aryl, Organic Chemistry, Regioselectivity, 010402 general chemistry, 01 natural sciences, Nmr data, Combinatorial chemistry, Catalysis, 0104 chemical sciences, chemistry.chemical_compound, chemistry, Isothiocyanate, Organic chemistry, Acetamide
Abstract

Multifunctionalized 2-imino-3-(pyrazol-4-yl)thiazolidin-4-ones and 2-arylimino-3-(pyrazol-4-yl)thiazolidin-4-ones were prepared according to an efficient four-step procedure. The key step of the synthetic pathway involved the cyclization of 2-chloro-N-(pyrazol-4-yl)acetamide intermediate using KSCN or aryl isothiocyanate, respectively. The structure of the title compounds was confirmed on the basis of NMR data and 15N-labeling.

Published
2016
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16. Bacterial Transferase MraY, a Source of Inspiration towards New Antibiotics

Author

Nicolas Pietrancosta, Sandrine Calvet-Vitale, Nathalie Evrard-Todeschi, Christine Gravier-Pelletier, Laurent Le Corre, Ahmed Bouhss, Mickaël J Fer, Samir Olatunji, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Trinity College Dublin, Structure et activité des biomolécules normales et pathologiques (SABNP), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE), Centre d'Ingénierie des Protéines, Université de Liège-Institut de Chimie B6, Enveloppes Bactériennes et Antibiotiques (ENVBAC), Département Microbiologie (Dpt Microbio), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Systèmes glutamatergiques normaux et pathologiques = Normal and Pathologic Glutamatergic Neurons (NPS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Chimie Moléculaire de Paris Centre (FR 2769), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
nucleoside antibiotics, Research groups, medicine.drug_class, [SDV]Life Sciences [q-bio], Antibiotics, Transferases (Other Substituted Phosphate Groups), Computational biology, Peptidoglycan, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biology, 01 natural sciences, Biochemistry, MraY, Structure-Activity Relationship, Antibiotic resistance, Bacterial Proteins, biological evaluations, Transferases, Drug Discovery, medicine, Transferase, Peptidoglycan biosynthesis, Enzyme Inhibitors, triazoles, ComputingMilieux_MISCELLANEOUS, Pharmacology, Binding Sites, Bacteria, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, 3. Good health, 0104 chemical sciences, Anti-Bacterial Agents, molecular modelling, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, Docking (molecular), Drug Design, docking, Molecular Medicine, mutagenesis
Abstract

The bacterial resistance to antibiotics constitutes more than ever a severe public health problem. The enzymes involved in bacterial peptidoglycan biosynthesis are pertinent targets for developing new antibiotics, notably the MraY transferase that is not targeted by any marketed drug. Many research groups are currently working on the study or the inhibition of this enzyme. After a concise overview of the role, mechanism and inhibition of MraY, the structure–activity relationships of 5’-triazole-containing aminoribosyluridine inhibitors, we previously synthetized, will be presented. The recently published MraY X-ray structures allowed us to achieve a molecular virtual high-throughput screening of commercial databases and our in-house library resulting in the identification of promising compounds for the further development of new antibiotics.

Published
2018
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17. 5′-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling

Author

Ahmed Bouhss, Nicolas Pietrancosta, Christine Gravier-Pelletier, Dominique Mengin-Lecreulx, Ana Maria Amoroso, Sandrine Calvet-Vitale, Laurent Le Corre, Bernard Joris, Mariana Patrão, Michael Fer, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Enveloppes Bactériennes et Antibiotiques (ENVBAC), Département Microbiologie (Dpt Microbio), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Unité de Physiologie et Génétique Bactériennes, Centre d'Ingénierie des Protéines, Département des Sciences de la Vie, Université de Liège, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques ( LCBPT - UMR 8601 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Enveloppes Bactériennes et Antibiotiques ( ENVBAC ), Département Microbiologie ( Dpt Microbio ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay

Subjects
Models, Molecular, Molecular model, Stereochemistry, [SDV]Life Sciences [q-bio], Triazole, Transferases (Other Substituted Phosphate Groups), Alkyne, Chemistry Techniques, Synthetic, Microbial Sensitivity Tests, 010402 general chemistry, 01 natural sciences, Biochemistry, chemistry.chemical_compound, Bacterial Proteins, Transferases, Catalytic Domain, Enzyme Inhibitors, Physical and Theoretical Chemistry, Methylene, Uridine, chemistry.chemical_classification, [ SDV ] Life Sciences [q-bio], 010405 organic chemistry, Organic Chemistry, Biological activity, Triazoles, Cycloaddition, Anti-Bacterial Agents, 0104 chemical sciences, chemistry, Azide, Antibacterial activity, Bacillus subtilis
Abstract

International audience; The straightforward synthesis of 5'-methylene-[1,4]-triazole-substituted aminoribosyl uridines is described. Two families of compounds were synthesized from a unique epoxide which was regioselectively opened by acetylide ions (for compounds II) or azide ions (for compounds III). Sequential diastereoselective glycosylation with a ribosyl fluoride derivative, Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) with various complementary azide and alkyne partners afforded the targeted compounds after final deprotection. The biological activity of the 16 resulting compounds together with that of 14 previously reported compounds I, lacking the 5' methylene group, was evaluated on the MraY transferase activity. Out of the 30 tested compounds, 18 compounds revealed MraY inhibition with IC50 ranging from 15 to 150 μM. A molecular modeling study was performed to rationalize the observed structure-activity relationships (SAR), which allowed us to correlate the activity of the most potent compounds with an interaction involving Leu191 of MraYAA. The antibacterial activity was also evaluated and seven compounds exhibited a good activity against Gram-positive bacterial pathogens with MIC ranging from 8 to 32 μg mL(-1), including the methicillin resistant Staphylococcus aureus (MRSA).

Published
2015
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18. Microwave-assisted preparation of 4-amino-3-cyano-5-methoxycarbonyl-N-arylpyrazoles as building blocks for the diversity-oriented synthesis of pyrazole-based polycyclic scaffolds

Author

Arthur Guillard, Patricia Busca, Guillaume Prestat, Christine Gravier-Pelletier, Laurent Le Corre, and Lotfi Tak-Tak

Subjects
Spectrometry, Mass, Electrospray Ionization, chemistry.chemical_compound, Magnetic Resonance Spectroscopy, chemistry, Stereochemistry, Organic Chemistry, Pyrazoles, Physical and Theoretical Chemistry, Pyrazole, Microwaves, Biochemistry, Combinatorial chemistry, Microwave assisted
Abstract

The synthesis of 4-amino-3-cyano-N-arylpyrazoles A based on a Thorpe-Ziegler cyclization as the key step has been achieved using microwave activation. Via a new diversity-oriented synthetic pathway, these highly functionalized building blocks allowed the access to various heteroaromatic scaffolds such as pyrazolo-pyridines B, pyrazolo-pyrimidines C and pyrazolo-oxadiazoles D. Interestingly, these platforms contain three to four reactive sites that could be used for post-functionalization in order to further increase the molecular diversity.

Published
2015
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19. Towards New MraY Inhibitors: A Serine Template for Uracil and 5-Amino-5-deoxyribosyl Scaffolding

Author

Laurent Le Corre, Yves Le Merrer, and Christine Gravier-Pelletier

Subjects
chemistry.chemical_classification, biology, Stereochemistry, Organic Chemistry, Uracil, Reductive amination, Uridine, Amino acid, Serine, chemistry.chemical_compound, Enzyme, chemistry, biology.protein, Moiety, Translocase, Physical and Theoretical Chemistry
Abstract

The bacterial translocase MraY is a good target for the development of new antitbiotics as it is ubiquitous and essential for bacterial growth. The goal of this work was the synthesis of simplified analogues of naturally occurring inhibitors of this enzyme to investigate the essential character of the uridine moiety of these inhibitors with regards to biological activity. Thus, the structure of the targeted enantiomerically pure N-(uracilylpentyl)-β-D-O-(5-amino-5-deoxyribosyl)-L-serine retains uracil and 5-amino-5-deoxyribose parts linked by a serinyl template. The synthetic strategy towards this compound relies on sequential O-glycosylation and N-alkylation by reductive amination of a serine derivative. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Published
2007
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20. ChemInform Abstract: Microwave-Assisted Preparation of 4-Amino-3-cyano-5-methoxycarbonyl-N-arylpyrazoles as Building Blocks for the Diversity-Oriented Synthesis of Pyrazole-Based Polycyclic Scaffolds

Author

Lotfi Tak-Tak, Arthur Guillard, Christine Gravier-Pelletier, Patricia Busca, Laurent Le Corre, and Guillaume Prestat

Subjects
chemistry.chemical_compound, chemistry, Aryl, General Medicine, Pyrazole, Combinatorial chemistry, Microwave assisted
Abstract

Starting from variously substituted aryl amines a two-step approach to compounds (V) is developed.

Published
2015
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21. Synthesis and In Vitro Antitumor Activity of Novel Ring D Analogues of the Marine Pyridoacridine Ascididemin: Structure−Activity Relationship

Author

Françoise Collignon, Laurent Le Corre, Robert Kiss, Sylvie Bayssade, and Armand Frydman, Philippe Portefaix, Anne Bouteillé, Francis Darro, Jean Bastide, Chantal Galaup, Evelyne Delfourne, and Brigitte Lesur

Subjects
Tertiary amine, Nitro compound, Antineoplastic Agents, Chemical synthesis, Inhibitory Concentration 50, Mice, Structure-Activity Relationship, Alkaloids, In vivo, Drug Discovery, Tumor Cells, Cultured, Animals, Humans, Structure–activity relationship, Cytotoxicity, chemistry.chemical_classification, Chemistry, Aromatic amine, In vitro, Biochemistry, Quinolines, Acridines, Molecular Medicine, Drug Screening Assays, Antitumor, Cell Division, Phenanthrolines
Abstract

Marine compounds with pyridoacridine skeletons are known to exhibit interesting antitumor activities. Ascididemin has already been reported as displaying significant antitumor activities in vitro and has also been found to have a relatively high global toxicity in vivo. We synthesized a series of 16 analogues (among which 11 compounds were different from previously described ones) with the aim of developing new anticancer agents with significantly improved efficacy/tolerability ratios. These compounds were obtained either by total synthesis from 5,8-quinolinedione and substituted 2-aminoacetophenones or by the direct substitution of ascididemin. The different compounds and ascididemin used as the control compound were tested at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate, and bladder cancers). The IC(50) value (i.e., the drug concentration inhibiting the mean growth value of the 12 cell lines by 50%) of these compounds ranged over five log concentrations, i.e., between 10 000 and 0.1 nM. For several new chemical entities, the antitumor activity (determined in vitro) and tolerability (determined in vivo) were superior to those of the parent alkaloids, i.e., ascididemin and 2-bromoleptoclinidone.

Published
2002
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22. Molecular modeling study of the induced-fit effect on kinase inhibition: the case of fibroblast growth factor receptor 3 (FGFR3)

Author

Laurence Legeai-Mallet, Guillaume Prestat, Florent Barbault, Yan Li, Rongjing Hu, Ruisheng Zhang, Michel Delamar, Laurent Le Corre, and Patricia Busca

Subjects
Models, Molecular, Conformational change, biology, Molecular model, Kinase, Chemistry, Protein Conformation, Reproducibility of Results, Fibroblast growth factor receptor 3, Molecular Dynamics Simulation, Ligands, Receptor tyrosine kinase, Computer Science Applications, Molecular Docking Simulation, Biochemistry, Protein kinase domain, Drug Discovery, Helix, biology.protein, Biophysics, Receptor, Fibroblast Growth Factor, Type 3, Physical and Theoretical Chemistry, Tyrosine kinase, Protein Kinase Inhibitors
Abstract

Tyrosine kinases are a wide family of targets with strong pharmacological relevance. These proteins undergo large-scale conformational motions able to inactivate them. By the end of one of these structural processes, a new cavity is opened allowing the access to a specific type of inhibitors, called type II. The kinase domain of fibroblast growth factor receptor 3 (FGFR3) falls into this family of kinases. We describe here, for the first time, its inactivation process through target molecular dynamics. The transient cavity, at the crossroad between the DFGout and Cα helix out inactivation is herein explored. Molecular docking calculations of known ligands demonstrated that type II inhibitors are able to interact with this metastable transient conformation of FGFR3 kinase. Besides, supplemental computations were conducted and clearly show that type II inhibitors drive the kinase inactivation process through specific stabilization with the DFG triad. This induced-fit effect of type II ligands toward FGFR3 might be extrapolated to other kinase systems and provides meaningful structural information for future drug developments.

Published
2014

23. Synthesis of 5-substituted pipecolic acid derivatives as new conformationally constrained ornithine and arginine analogues

Author

Laurent Le Corre and H. Dhimane

Subjects
chemistry.chemical_compound, Arginine, chemistry, Stereochemistry, Organic Chemistry, Drug Discovery, Electrophile, Organic chemistry, Ornithine, Biochemistry, Pipecolic acid
Abstract

Two, orthogonally protected, constrained analogues of arginine have been synthesised in a diastereodivergent manner. The key step involved an electrophilic or radical functionalisation of methyl N-Boc-5,6-dehydropipecolate.

Published
2005
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24. A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model

Author

Catherine Benoist-Lasselin, Anne-Lise Girard, Arnold Munnich, Patricia Busca, Laurent Schibler, Emilie Mugniery, Laurence Legeai-Mallet, Laurent Le Corre, Yves Le Merrer, Nabil Kaci, Aurélie Jonquoy, Florent Barbault, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Interfaces, Traitements, Organisation et Dynamique des Systèmes (ITODYS (UMR_7086)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques ( LCBPT - UMR 8601 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire ITODYS, Université Paris Diderot - Paris 7 ( UPD7 ), Génétique Animale et Biologie Intégrative ( GABI ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, AgroParisTech-Institut National de la Recherche Agronomique (INRA), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Diderot - Paris 7 (UPD7)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Pyridines, Cell Cycle Proteins, Fibroblast growth factor, Receptor tyrosine kinase, Tyrosine-kinase inhibitor, Mice, 0302 clinical medicine, Femur, Growth Plate, Phosphorylation, [ SDV.SA ] Life Sciences [q-bio]/Agricultural sciences, Genetics (clinical), Bone growth, 0303 health sciences, biology, Cell Differentiation, General Medicine, Cell cycle, musculoskeletal system, 3. Good health, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Models, Animal, dysplasia type-i, musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, medicine.drug_class, In Vitro Techniques, Chondrocyte, Cell Line, 03 medical and health sciences, Chondrocytes, Internal medicine, Proliferating Cell Nuclear Antigen, Genetics, medicine, Animals, Receptor, Fibroblast Growth Factor, Type 3, plate chondrocyte, Molecular Biology, Endochondral ossification, Protein Kinase Inhibitors, 030304 developmental biology, Cell Proliferation, Bone Development, hypertrophic differentiation, Fibroblast growth factor receptor 3, stomatognathic diseases, Endocrinology, Pyrimidines, Protein Biosynthesis, factor receptor-3 fgfr3, biology.protein, mutation
Abstract

Chantier qualité GA; Activating germline fibroblast growth factor receptor 3 (FGFR3) mutations cause achondroplasia (ACH), the most common form of human dwarfism and a spectrum of skeletal dysplasias. FGFR3 is a tyrosine kinase receptor and constitutive FGFR3 activation impairs endochondral ossification and triggers severe disorganization of the cartilage with shortening of long bones. To decipher the role of FGFR3 in endochondral ossification, we analyzed the impact of a novel tyrosine kinase inhibitor (TKI), A31, on both human and mouse mutant FGFR3-expressing cells and on the skeleton of Fgfr3Y367C/+ dwarf mice. We found that A31 inhibited constitutive FGFR3 phosphorylation and restored the size of embryonic dwarf femurs using an ex vivo culture system. The increase in length of the treated mutant femurs was 2.6 times more than for the wild-type. Premature cell cycle exit and defective chondrocyte differentiation were observed in the Fgfr3Y367C/+ growth plate. A31 restored normal expression of cell cycle regulators (proliferating cell nuclear antigen, KI67, cyclin D1 and p57) and allowed pre-hypertrophic chondrocytes to properly differentiate into hypertrophic chondocytes. Our data reveal a specific role for FGFR3 in the cell cycle and chondrocyte differentiation and support the development of TKIs for the treatment of FGFR3-related chondrodysplasias.

Published
2012
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25. Synthesis and biological evaluation of a triazole-based library of pyrido[2,3-d]pyrimidines as FGFR3 tyrosine kinase inhibitors

Author

Yves Le Merrer, François Radvanyi, Aurélie Jonquoy, Catherine Benoist-Lasselin, Laurent Le Corre, Emilie Mugniery, Anne-Lise Girard, Patricia Busca, Laurence Legeai-Mallet, and Johannes Aubertin

Subjects
Stereochemistry, Pyridines, Mutant, Triazole, Biochemistry, Cell Line, Small Molecule Libraries, chemistry.chemical_compound, Structure-Activity Relationship, Structure–activity relationship, Humans, Physical and Theoretical Chemistry, Binding site, Kinase activity, Protein Kinase Inhibitors, Binding Sites, Molecular Structure, Organic Chemistry, HEK 293 cells, Stereoisomerism, Protein-Tyrosine Kinases, Triazoles, In vitro, Recombinant Proteins, Pyrimidines, chemistry, Drug Design, Tyrosine kinase
Abstract

A library of pyrido[2,3-d]pyrimidines was designed as inhibitors of FGFR3 tyrosine kinase allowing possible interactions with an unexploited region of the ATP binding-site. This library was built-up with an efficient step of click-chemistry giving easy access to triazole-based compounds bearing a large panel of substituents. Among the 27 analogues synthesized, more than half exhibited 55-89% inhibition of in vitro FGFR3 kinase activity at 2 microM and one (19g) was able to inhibit auto-phosphorylation of mutant FGFR3-K650M in transfected HEK cells.

Published
2010

26. Diastereoselective functionalizations of enecarbamates derived from pipecolic acid towards 5-guanidinopipecolates as arginine mimetics

Author

Camille Levraud, Hamid Dhimane, Véronique Bonnet, Laurent Le Corre, Jean-Claude Kizirian, and Jean-Luc Boucher

Subjects
Azides, Double bond, Arginine, Stereochemistry, Hydroxylation, Biochemistry, chemistry.chemical_compound, Nos isoforms, Biomimetic Materials, Physical and Theoretical Chemistry, Amines, Enzyme Inhibitors, Guanidine, Pipecolic acid, chemistry.chemical_classification, biology, Molecular Structure, Organic Chemistry, Stereoisomerism, Ketones, Nitric oxide synthase, chemistry, Pipecolic Acids, Electrophile, biology.protein, Carbamates, Nitric Oxide Synthase, Oxidation-Reduction
Abstract

Various substituents could be diastereoselectively introduced into the 5-position of pipecolic acid via electrophilic or free-radical-initiated addition to the carbon–carbon double bond of endocyclic enecarbamates derived from pipecolic acid. This study allowed the diastereoselective synthesis of both cis- and trans-5-guanidino pipecolates, which were designed as constrained arginine mimetics and whose potential inhibition of nitric oxide synthase (NOS) was evaluated with three NOS isoforms.

Published
2008

27. The heptahelical domain of GABA(B2) is activated directly by CGP7930, a positive allosteric modulator of the GABA(B) receptor

Author

Laurent Prézeau, Virginie Binet, Jean-Philippe Pin, Laurent Le Corre, Francine Acher, Carole Brajon, Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Prezeau, Laurent, Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS) - Université Montpellier 2 - Sciences et Techniques (UM2) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Montpellier 1 (UM1) - Université de Montpellier (UM), Laboratoire de génomique fonctionnelle (LGF), Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5) - Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: gamma-Aminobutyric Acid, Ligands, Biochemistry, MESH: Allosteric Regulation, MESH: Dose-Response Relationship, Drug, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH: Phenols, MESH: Ligands, MESH: Animals, Receptor, MESH: Receptors, GABA-B, gamma-Aminobutyric Acid, 0303 health sciences, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Protein Subunits, Cell biology, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Mutagenesis, Site-Directed, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Dimerization, medicine.drug, Agonist, Allosteric modulator, MESH: GTP-Binding Proteins, medicine.drug_class, Inositol Phosphates, Allosteric regulation, Biology, GABAB receptor, Article, gamma-Aminobutyric acid, Cell Line, 03 medical and health sciences, Allosteric Regulation, Phenols, GTP-Binding Proteins, medicine, Animals, Humans, Homomeric, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, GABA-B Receptor Agonists, 030304 developmental biology, MESH: Humans, Dose-Response Relationship, Drug, Cell Biology, MESH: Inositol Phosphates, Protein Structure, Tertiary, MESH: Cell Line, Protein Subunits, Receptors, GABA-B, nervous system, MESH: Dimerization, Mutagenesis, Site-Directed, 030217 neurology & neurosurgery
Abstract

International audience; The gamma-aminobutyric acid, type B (GABA(B)) receptor is well recognized as being composed of two subunits, GABA(B1) and GABA(B2). Both subunits share structural homology with other class-III G-protein-coupled receptors. They are composed of two main domains: a heptahelical domain (HD) typical of all G-protein-coupled receptors and a large extracellular domain (ECD). Although GABA(B1) binds GABA, GABA(B2) is required for GABA(B1) to reach the cell surface. However, it is still not demonstrated whether the association of these two subunits is always required for function in the brain. Indeed, GABA(B2) plays a major role in the coupling of the heteromer to G-proteins, such that it is possible that GABA(B2) can transmit a signal in the absence of GABA(B1). Today only ligands interacting with GABA(B1) ECD have been identified. Thus, the compounds acting exclusively on the GABA(B2) subunit will be helpful in analyzing the specific role of this subunit in the brain. Here, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABA(B) receptor. We showed that it activates the wild type GABA(B) receptor but with a low efficacy. The GABA(B2) HD is necessary for this effect, although one cannot exclude that CGP7930 could also bind to GABA(B1). Of interest, CGP7930 could activate GABA(B2) expressed alone and is the first described agonist of GABA(B2). Finally, we show that CGP7930 retains its agonist activity on a GABA(B2) subunit deleted of its ECD. This demonstrates that the HD of GABA(B2) behaves similar to a rhodopsin-like receptor, because it can reach the cell surface alone, can couple to G-protein, and be activated by agonists. These data open new strategies for studying the mechanism of activation of GABA(B) receptor and examine any possible role of homomeric GABA(B2) receptors.

Published
2004
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28. Synthesis and in vitro antitumor activity of an isomer of the marine pyridoacridine alkaloid ascididemin and related compounds

Author

Francis Darro, Jean Bastide, Joumaa Merza, Armand Frydman, Laurent Le Corre, Robert Kiss, and Evelyne Delfourne

Subjects
Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Antineoplastic Agents, Marine Biology, Biochemistry, Chemical synthesis, Structure-Activity Relationship, Alkaloids, Isomerism, Prostate, Cell Line, Tumor, Drug Discovery, medicine, Cytotoxic T cell, Animals, Humans, Urochordata, Cytotoxicity, Molecular Biology, Chemistry, Alkaloid, Organic Chemistry, Ascididemin, In vitro, medicine.anatomical_structure, Cell culture, Quinolines, Molecular Medicine, Acridines, Drug Screening Assays, Antitumor, Cell Division, Phenanthrolines
Abstract

The isomer (9H-quino[4,3,2-de][1,7]phenanthroline-9-one) (2) of the marine alkaloid ascididemin (9H-quino[4,3,2-de][1,10]phenanthroline-9-one) (1) has been synthesized in six steps from 1,4-dimethoxyacridine (10) with an overall yield of 12%. Different related compounds were prepared and tested in vitro at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate and bladder cancers). Almost all the compounds present cytotoxic activity of micromolar order.

Published
2003

29. Un inventaire du patrimoine naturel : les Z.N.I.E.F.F

Author

Laurent Le Corre and Arnaud Noury

Subjects
General Medicine
Abstract

Natural areas of interest for their ecology, flora or fauna (« ZN.I.EF.F.s »), the main element of the national inventory of natural heritage, raise many questions about their legal character and scope. In response to these questions, the State has tried to make up for the lack of original formalization but has not managed to do so completely because their legal doctrine is itself somewhat ambiguous. Nevertheless, the fact that the pioneers of the inventory were not wholly clear about these questions does not prevent the Z.N.I.EF.F. from being considered as administrative documents comprising straightforward expert evaluations. However, their use by administrative courts has provoked strong reactions, although an analysis of the case-law clearly shows that Z.N.I.E.F.F.s have only been used by these courts as instruments demonstrating the ecological value of some habitats. It remains to be seen whether the second generation of ZN.I.EF.F.s, now in the course of preparation, will be able to be used in legal proceedings in this way., Les Z.N.I.E.F.F., élément central de l'inventaire du patrimoine naturel national, suscitent bien des interrogations concernant aussi bien leur nature que leur portée juridiques. Pour répondre aux interrogations, l'administration a tenté de pallier l'absence de formalisation originelle sans toutefois y parvenir complètement puisque sa doctrine n'est pas elle-même sans ambiguïté. L'absence d'une totale clarté concernant ces questions chez les initiateurs de l'inventaire n'empêche pas cependant de considérer les Z.N.I.E.F.F. comme des documents administratifs constituant de simples expertises. Cependant, leur utilisation par les juridictions administratives a provoqué de vives réactions. L'analyse de la jurisprudence montre pourtant clairement que les Z.N.I.E.F.F. n'ont été utilisées par les juridictions qu'en tant qu'instruments de connaissance de la valeur écologique des milieux. Reste à déterminer si la deuxième génération de Z.N.I.E.F.F. en préparation permettra un tel usage contentieux., Le Corre Laurent, Noury Arnaud. Un inventaire du patrimoine naturel : les Z.N.I.E.F.F.. In: Revue Juridique de l'Environnement, n°4, 1996. pp. 387-407.

Published
1996

30. Persulfidation of DJ-1: Mechanism and Consequences

Author

Erwan Galardon, Nicolas Mathas, Dominique Padovani, Laurent Le Corre, Gabrielle Poncet, and Julien Dairou

Subjects
persulfide, DJ-1, hydrogen sulfide, sulfinic, Molecular Biology, Biochemistry
Abstract

DJ-1 (also called PARK7) is a ubiquitously expressed protein involved in the etiology of Parkinson disease and cancers. At least one of its three cysteine residue is functionally essential, and its oxidation state determines the specific function of the enzyme. DJ-1 was recently reported to be persulfidated in mammalian cell lines, but the implications of this post-translational modification have not yet been analyzed. Here, we report that recombinant DJ-1 is reversibly persulfidated at cysteine 106 by reaction with various sulfane donors and subsequently inhibited. Strikingly, this reaction is orders of magnitude faster than C106 oxidation by H2O2, and persulfidated DJ-1 behaves differently than sulfinylated DJ-1. Both these PTM most likely play a dedicated role in DJ-1 signaling or protective pathways.

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