Search

Your search keyword '"Matthieu Montes"' showing total 20 results
Start Over Author "Matthieu Montes" Topic biology
20 results on '"Matthieu Montes"'

1. High-Resolution Mining of SARS-CoV-2 Main Protease Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

Author

Pengyu Ren, Chengwen Liu, Louis Lagardère, Théo Jaffrelot Inizan, Dina El Ahdab, Frédéric Célerse, Luc-Henri Jolly, Matthieu Montes, Olivier Adjoua, Pierre Monmarché, Nathalie Lagarde, Jean-Philip Piquemal, Laboratoire de chimie théorique (LCT), Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Parisien de Chimie Physique et Théorique (IP2CT), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Biomedical Engineering [Austin], University of Texas at Austin [Austin], Laboratoire Génomique, bioinformatique et chimie moléculaire (GBCM), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), European Project: 810367,EMC2(2019), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
Adaptive sampling, [PHYS.MPHY]Physics [physics]/Mathematical Physics [math-ph], SARS-COV-2, Protomer, Molecular dynamics, Polarizable force field AMOEBA, 01 natural sciences, 03 medical and health sciences, 0103 physical sciences, Amoeba (mathematics), Cluster analysis, 030304 developmental biology, Physics, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], 010304 chemical physics, biology, Solvation, COVID-19, Active site, General Chemistry, AMOEBA, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Chemistry, main protease, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Oxyanion hole, Biological system, Mpro
Abstract

We provide an unsupervised adaptive sampling strategy capable of producing μs-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFFs). The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within a selective process to achieve sufficient phase-space sampling. Accurate statistical properties can be obtained through reweighting. Within this highly parallel setup, the Tinker-HP package can be powered by an arbitrary large number of GPUs on supercomputers, reducing exploration time from years to days. This approach is used to tackle the urgent modeling problem of the SARS-CoV-2 Main Protease (Mpro) producing more than 38 μs of all-atom simulations of its apo (ligand-free) dimer using the high-resolution AMOEBA PFF. The first 15.14 μs simulation (physiological pH) is compared to available non-PFF long-timescale simulation data. A detailed clustering analysis exhibits striking differences between FFs, with AMOEBA showing a richer conformational space. Focusing on key structural markers related to the oxyanion hole stability, we observe an asymmetry between protomers. One of them appears less structured resembling the experimentally inactive monomer for which a 6 μs simulation was performed as a basis for comparison. Results highlight the plasticity of the Mpro active site. The C-terminal end of its less structured protomer is shown to oscillate between several states, being able to interact with the other protomer, potentially modulating its activity. Active and distal site volumes are found to be larger in the most active protomer within our AMOEBA simulations compared to non-PFFs as additional cryptic pockets are uncovered. A second 17 μs AMOEBA simulation is performed with protonated His172 residues mimicking lower pH. Data show the protonation impact on the destructuring of the oxyanion loop. We finally analyze the solvation patterns around key histidine residues. The confined AMOEBA polarizable water molecules are able to explore a wide range of dipole moments, going beyond bulk values, leading to a water molecule count consistent with experimental data. Results suggest that the use of PFFs could be critical in drug discovery to accurately model the complexity of the molecular interactions structuring Mpro., We provide an unsupervised adaptive sampling strategy capable of producing μs-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFFs).

Published
2021
Full Text
View/download PDF

2. Neuropilin 1 and Neuropilin 2 gene invalidation or pharmacological inhibition reveals their relevance for the treatment of metastatic renal cell carcinoma

Author

Nathalie Lagarde, Marina Pagnuzzi-Boncompagni, Valérie Vial, Matthieu Montes, Christiane Garbay, Gilles Pagès, Aurore Dumond, Jérôme Durivault, Olivier Hermine, Yves Lepelletier, Renaud Grépin, Anna K. Puszko, Etienne Brachet, Christopher Montemagno, Luc Demange, Brachet, Etienne, Laboratoire International Associé Réponse des Organismes et Populations face au Stress Environnemental - Université Côte d’Azur - Centre Scientifique de Monaco (LIA ROPSE), Université Côte d’Azur - Centre Scientifique de Monaco, Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Laboratoire Génomique, bioinformatique et chimie moléculaire (GBCM), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), HESAM Université (HESAM), and Université Nice Sophia Antipolis (... - 2019) (UNS)

Subjects
0301 basic medicine, Models, Molecular, Cancer Research, Neuropilins, medicine.medical_treatment, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Gene Knockout Techniques, Mice, 0302 clinical medicine, Cell Movement, Neuropilin 1, Neoplasm Metastasis, Cancer, Sunitinib, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Kidney Neoplasms, 3. Good health, Vascular endothelial growth factor A, Vascular endothelial growth factor C, Oncology, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, medicine.drug, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, Carcinoma, Renal Cell, Cell Proliferation, Research, ccRCC, Immunotherapy, medicine.disease, Xenograft Model Antitumor Assays, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Neuropilin-1, Neuropilin-2, Clear cell renal cell carcinoma, 030104 developmental biology, Cancer research
Abstract

Background Despite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent®), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (NRP1, 2) are expressed on several tumor cells including ccRCC. We analyzed the role of the VEGFs/NRPs signaling in ccRCC aggressiveness and evaluated the relevance to target this pathway. Methods We correlated the NRP1, 2 levels to patients’ survival using online available data base. Human and mouse ccRCC cells were knocked-out for the NRP1 and NRP2 genes by a CRISPR/Cas9 method. The number of metabolically active cells was evaluated by XTT assays. Migration ability was determined by wound closure experiments and invasion ability by using Boyden chamber coated with collagen. Production of VEGFA and VEGFC was evaluated by ELISA. Experimental ccRCC were generated in immuno-competent/deficient mice. The effects of a competitive inhibitor of NRP1, 2, NRPa-308, was tested in vitro and in vivo with the above-mentioned tests and on experimental ccRCC. NRPa-308 docking was performed on both NRPs. Results Knock-out of the NRP1 and NRP2 genes inhibited cell metabolism and migration and stimulated the expression of VEGFA or VEGFC, respectively. NRPa-308 presented a higher affinity for NRP2 than for NRP1. It decreased cell metabolism and migration/invasion more efficiently than sunitinib and the commercially available NRP inhibitor EG00229. NRPa-308 presented a robust inhibition of experimental ccRCC growth in immunocompetent and immunodeficient mice. Such inhibition was associated with decreased expression of several pro-tumoral factors. Analysis of the TCGA database showed that the NRP2 pathway, more than the NRP1 pathway correlates with tumor aggressiveness only in metastatic patients. Conclusions Our study strongly suggests that inhibiting NRPs is a relevant treatment for mccRCC patients in therapeutic impasses and NRPa-308 represents a relevant hit.

Published
2021
Full Text
View/download PDF

3. NRPa-308, a new neuropilin-1 antagonist, exerts in vitro anti-angiogenic and anti-proliferative effects and in vivo anti-cancer effects in a mouse xenograft model

Author

Rachid Benhida, Wang-Qing Liu, Sylvie Dufour, Yves Lepelletier, Olivier Hermine, Bertrand Leforban, Renaud Grépin, Françoise Raynaud, Luc Demange, Christiane Garbay, Rafika Jarray, Matthieu Montes, Ali Loukaci, Gilles Pagès, Réda Hadj-Slimane, and Lucia Borriello

Subjects
0301 basic medicine, Cancer Research, Angiogenesis, Angiogenesis Inhibitors, Mice, SCID, Pharmacology, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Mice, Inbred NOD, In vivo, Cell Line, Tumor, Neoplasms, Neuropilin 1, medicine, Animals, Humans, Cytotoxic T cell, Viability assay, Cells, Cultured, Cell Proliferation, Mice, Knockout, Molecular Structure, Sunitinib, Cancer, medicine.disease, Survival Analysis, Xenograft Model Antitumor Assays, Neuropilin-1, Tumor Burden, Vascular endothelial growth factor, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, medicine.drug
Abstract

Neuropilin-1 (NRP-1) is an extra-cellular receptor for the main Vascular Endothelial Growth Factor over-expressed in tumour tissues, VEGF-A165. Consequently, NRP-1 is involved in angiogenesis and in tumour growth, and its over-expression is related to a clinical poor prognosis. NRP-1 appears as a major target in oncology, which remains poorly exploited. Herein, we report a new series of 18 small-sized fully organic VEGF-A165/NRP-1 antagonists (NRPas). These compounds share an original scaffold, including two linkers (sulphonamide and amide) and three aromatic cores. Among them, 2a (renamed NRPa-308) emerges as a promising “hit”. In vitro, 2a exerts not only potent anti-angiogenic activity, but also significant effects on cell viability of large panel of human solid and haematological cancer cell lines. Importantly, 2a is less cytotoxic on healthy tissues than the marketed anti-angiogenic drug sunitinib. Lastly, in a mouse xenograft model (human MDA-MB-231 breast cancer cells), 2a improves the median survival and reduces the tumour growth, but does not exert visible acute toxicity. Altogether, these results highlight its huge potential for a further “hit-to-lead” optimization, leading to new anti-cancer drugs.

Published
2018
Full Text
View/download PDF

4. New selective cyclooxygenase-2 inhibitors from cyclocoumarol: Synthesis, characterization, biological evaluation and molecular modeling

Author

Anita Marie Rayar, Florent Blanchard, Matthieu Montes, Maité Sylla-Iyarreta Veitía, Nathalie Lagarde, Jean-François Zagury, Clotilde Ferroud, Bertrand Liagre, Frederique Martin, Laboratoire de Chimie moléculaire, génie des procédés chimiques et énergétiques (CMGPCE), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Laboratoire génomique, bioinformatique et applications (GBA), PEIRENE (PEIRENE), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centre Resource Autisme Bourgogne, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Chimie des Substances Naturelles (LCSN), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Université de Lille, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Centre d'enseignement Cnam Paris (CNAM Paris)

Subjects
Models, Molecular, Molecular model, Stereochemistry, medicine.drug_class, chemistry.chemical_element, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Oxygen, Anti-inflammatory, Structure-Activity Relationship, Drug Discovery, medicine, [CHIM]Chemical Sciences, Binding site, ComputingMilieux_MISCELLANEOUS, Pharmacology, chemistry.chemical_classification, biology, Cyclooxygenase 2 Inhibitors, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Hydrogen bond, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, General Medicine, 4-Hydroxycoumarins, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Enzyme, chemistry, Docking (molecular), Cyclooxygenase 2, biology.protein, Cyclooxygenase, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract

International audience; In this work, a serie of cyclocoumarol derivatives was designed, synthesized, characterized and studied for their potentialities as selective inhibitors of COX-2. All target compounds have been screened for their anti-inflammatory activity by the assay of PGE2 production. Among them, compound 5d exhibited the most potent inhibitory activity with a PGE2 inhibition compared to NS-398 (79% and 88% respectively) and showed non-inhibitory activity towards the COX-1 enzyme. Docking studies revealed the capacity of this compound to occupy the selective COX-2 cavity establishing additional hydrogen bonds between the oxygen of the methoxy group and the His90 and Arg513 of the binding site of the enzyme.

Published
2018
Full Text
View/download PDF

5. Identification of an in vivo orally active dual-binding protein-protein interaction inhibitor targeting TNFα through combined in silico/in vitro/in vivo screening

Author

Rojo Ratsimandresy, Lucille Desallais, Patrick Gizzi, Chouki Zerrouki, Jean Louis Spadoni, Hervé Do, Jean-François Zagury, Bruno Baron, Julie Perrier, Hélène Guillemain, Nesrine Ben Nasr, Matthieu Montes, Patrick England, Najla Fourati, Hadley Mouhsine, Gabriel Moreau, Laboratoire génomique, bioinformatique et applications (GBA), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Service de rhumatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Peptinov, Peptinov SAS, H.G. and H.M. are recipients of CIFRE fellowships from Association Nationale de la Recherche et de la Technologie (ANRT). J.P. and N.B.N are recipients of fellowships from the French Ministère de l’Enseignement Supérieur et de la Recherche (MESR). This work was funded in part by grants from Conservatoire National des Arts et Métiers and from Peptinov SAS., We would like to thank Prof. Jain for providing Surflex, and Chemaxon for providing the Marvin suite. We would like to thank O. De Oliveira for her technical support during the in vivo experiments, Prestwick Chemical and CMGPCE, CNAM for their support in analytical chemistry and the HistIM platform for technical support with the immunochemistry and histology experiments., Autard, Delphine, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS), Biophysique des macromolécules et leurs interactions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), EQUIPE GÉNOMIQUE, BIOINFORMATIQUE ET PATHOLOGIES DU SYSTÈME IMMUNITAIRE, École normale supérieure - Cachan (ENS Cachan) - Université Paris-Sud - Paris 11 (UP11) - Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR) - École normale supérieure - Rennes (ENS Rennes) - Université de Cergy Pontoise - Conservatoire National des Arts et Métiers [CNAM] (CNAM) - Centre National de la Recherche Scientifique (CNRS), Biophysique Moléculaire (Plate-forme), Institut Pasteur [Paris] - Centre National de la Recherche Scientifique (CNRS), Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS) - Centre National de la Recherche Scientifique (CNRS), This work was funded in part by grants from Conservatoire National des Arts et Métiers and from Peptinov SAS., Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Anti-Inflammatory Agents, Drug Evaluation, Preclinical, Administration, Oral, Pharmacology, Virtual drug screening, Receptors, Tumor Necrosis Factor, Mice, Applied immunology, analogs, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, Receptor, Mice, Inbred BALB C, Multidisciplinary, constants, 3. Good health, Molecular Docking Simulation, [SDV] Life Sciences [q-bio], Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Tumor necrosis factor alpha, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Protein Binding, Virtual screening, [SDV.IMM] Life Sciences [q-bio]/Immunology, Science, In silico, Biology, Article, necrosis-factor-alpha, drug discovery, Small Molecule Libraries, 03 medical and health sciences, Allosteric Regulation, In vivo, Cell Line, Tumor, Animals, Humans, suramin, Tumor Necrosis Factor-alpha, Binding protein, HEK 293 cells, In vitro, High-Throughput Screening Assays, HEK293 Cells, [INFO.INFO-BT] Computer Science [cs]/Biotechnology, 030104 developmental biology, Targeted drug delivery, potent, rheumatoid-arthritis, lymphotoxin-alpha
Abstract

TNFα is a homotrimeric pro-inflammatory cytokine, whose direct targeting by protein biotherapies has been an undeniable success for the treatment of chronic inflammatory diseases. Despite many efforts, no orally active drug targeting TNFα has been identified so far. In the present work, we identified through combined in silico/in vitro/in vivo approaches a TNFα direct inhibitor, compound 1, displaying nanomolar and micromolar range bindings to TNFα. Compound 1 inhibits the binding of TNFα with both its receptors TNFRI and TNFRII. Compound 1 inhibits the TNFα induced apoptosis on L929 cells and the TNFα induced NF-κB activation in HEK cells. In vivo, oral administration of compound 1 displays a significant protection in a murine TNFα-dependent hepatic shock model. This work illustrates the ability of low-cost combined in silico/in vitro/in vivo screening approaches to identify orally available small-molecules targeting challenging protein-protein interactions such as homotrimeric TNFα.

Published
2017
Full Text
View/download PDF

6. Dendritic cell-based therapeutic vaccine elicits polyfunctional HIV-specific T-cell immunity associated with control of viral load

Author

Yves Levy, Bryan King, Carson Harrod, Mathieu Surenaud, Lee Roberts, Sandra Zurawski, Matthieu Montes, Rodolphe Thiébaut, Sophie Pérusat, L Sloan, Constance Delaugerre, Geneviève Chêne, Amanda Cobb, Jacques Banchereau, Céline Boucherie, Karolina Palucka, Christine Lacabaratz, and Laura Richert

Subjects
0303 health sciences, Immunology, Dendritic cell, Biology, Virology, 3. Good health, Vaccination, 03 medical and health sciences, 0302 clinical medicine, Immune system, Viral replication, Antigen, 030220 oncology & carcinogenesis, Immunology and Allergy, Viral load, CD8, Ex vivo, 030304 developmental biology
Abstract

Efforts aimed at restoring robust immune responses limiting human immunodeficiency virus (HIV)-1 replication therapeutically are warranted. We report that vaccination with dendritic cells generated ex vivo and loaded with HIV lipopeptides in patients (n = 19) on antiretroviral therapy was well tolerated and immunogenic. Vaccination increased: (i) the breadth of the immune response from 1 (1-3) to 4 (2-5) peptide-pool responses/patient (p = 0.009); (ii) the frequency of functional T cells (producing at least two cytokines among IFN-γ, TNF-α, and IL-2) from 0.026 to 0.32% (p = 0.002) and from 0.26 to 0.35% (p = 0.005) for CD4(+) and CD8(+) T cells, respectively; and (iii) the breadth of cytokines secreted by PBMCs upon antigen exposure, including IL-2, IFN-γ, IL-21, IL-17, and IL-13. Fifty percent of patients experienced a maximum of viral load (VL) 1 log10 lower than the other half following antiretroviral treatment interruption. An inverse correlation was found between the maximum of VL and the frequency of polyfunctional CD4(+) T cells (p = 0.007), production of IL-2 (p = 0.006), IFN-γ (p = 0.01), IL-21 (p = 0.006), and IL-13 (p = 0.001). These results suggest an association between vaccine responses and a better control of viral replication. These findings will help in the development of strategies for a functional cure for HIV infection.

Published
2014
Full Text
View/download PDF

7. Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model

Author

Rafika Jarray, Christiane Garbay, Olivier Hermine, Serena Pavoni, Françoise Raynaud, Brigitte Delhomme, Jean Luc Boucher, Réda Hadj-Slimane, Bertrand Leforban, Yves Lepelletier, Lucia Borriello, Matthieu Montes, Luc Demange, Wang-Qing Liu, and Sylvie Dufour

Subjects
Models, Molecular, Vascular Endothelial Growth Factor A, Cancer Research, Neuropilins, In silico, Drug Evaluation, Preclinical, Antineoplastic Agents, Apoptosis, Breast Neoplasms, Mice, Transgenic, Mice, SCID, Pharmacology, Biology, Ligands, Small Molecule Libraries, Mice, Structure-Activity Relationship, Mice, Inbred NOD, In vivo, Cell Line, Tumor, Human Umbilical Vein Endothelial Cells, medicine, Animals, Humans, Kinase, Antagonist, Cancer, medicine.disease, Xenograft Model Antitumor Assays, Peptide Fragments, In vitro, Molecular Docking Simulation, Oncology, Disease Progression, Female
Abstract

Neuropilin-1/-2 (+33 NRPs), VEGF-A 165 co-receptors , are over-expressed during cancer progression. Thus, NRPs targeted drug development is challenged using a multistep in silico/in vitro screening procedure. The first fully non-peptidic VEGF-A 165 /NRPs protein–protein interaction antagonist (IC 50 = 34 μM) without effect on pro-angiogenic kinases has been identified (compound-1). This hit showed breast cancer cells anti-proliferative activity (IC 50 = 0.60 μM). Compound-1 treated NOG-xenografted mice significantly exerted tumor growth inhibition, which is correlated with Ki-67 low expression and apoptosis. Furthermore, CD31 + /CD34 + vessels are reduced in accordance with HUVEC-tube formation inhibition (IC 50 = 0.20 μM). Taking together, compound-1 is the first fully organic inhibitor targeting NRPs.

Published
2014
Full Text
View/download PDF

8. Immunization against an IL-6 peptide induces anti-IL-6 antibodies and modulates the Delayed-Type Hypersensitivity reaction in cynomolgus monkeys

Author

Hadley Mouhsine, Caroline Bouchez, Rojo Ratsimandresy, Jean-François Zagury, Lucille Desallais, Françoise Quintin-Colonna, Matthieu Montes, Gabriel Moreau, and Hervé Do

Subjects
0301 basic medicine, medicine.drug_class, Active immunization, Monoclonal antibody, Article, 03 medical and health sciences, 0302 clinical medicine, Hypersensitivity, Medicine, Animals, Humans, Multidisciplinary, biology, business.industry, Interleukin-6, Immunogenicity, Antibodies, Monoclonal, Antibodies, Neutralizing, Receptors, Interleukin-6, Hypersensitivity reaction, Macaca fascicularis, 030104 developmental biology, Immunization, Tetanus vaccine, 030220 oncology & carcinogenesis, Immunology, Antibody Formation, biology.protein, Anti-IL-6, Antibody, business, Peptides, medicine.drug
Abstract

Interleukin-6 (IL-6) overproduction has been involved in the pathogenesis of several chronic inflammatory diseases and the administration of an anti-IL-6 receptor monoclonal antibody has been proven clinically efficient to treat them. However, the drawbacks of monoclonal antibodies have led our group to develop an innovative anti-IL-6 strategy using a peptide-based active immunization. This approach has previously shown its efficacy in a mouse model of systemic sclerosis. Here the safety, immunogenicity and efficacy of this strategy was assessed in non human primates. No unscheduled death and clinical signs of toxicity was observed during the study. Furthermore, the cynomolgus monkeys immunized against the IL-6 peptide produced high levels of anti-IL-6 antibodies as well as neutralizing antibodies compared to control groups. They also showed an important decrease of the cumulative inflammatory score following a delayed-type hypersensitivity reaction induced by the Tetanus vaccine compared to control groups (minus 57,9%, P = 0.014). These findings are highly significant because the immunizing IL-6 peptide used in this study is identical in humans and in monkeys and this novel anti-IL-6 strategy could thus represent a promising alternative to monoclonal antibodies.

Published
2016
Full Text
View/download PDF

9. Multicohort Genomewide Association Study Reveals a New Signal of Protection Against HIV-1 Acquisition

Author

Daniëlle van Manen, Douglas A. Jabs, Ping An, Philippe Froguel, Sigrid Le Clerc, Jean-François Zagury, Cédric Coulonges, François Schächter, Taoufik Labib, Jean François Delfraissy, Sophie Limou, Lieng Taing, Jennifer L. Troyer, Jean Louis Spadoni, Leonard H. van den Berg, Olivier Delaneau, Matthieu Montes, Cheryl A. Winkler, Stephen J. O'Brien, Jan H. Veldink, Hanneke Schuitemaker, Efe Sezgin, Mark L. Van Natta, Susan Buchbinder, AII - Amsterdam institute for Infection and Immunity, and Experimental Immunology

Subjects
Adult, Male, viruses, Cytochrome P450 Family 7, HIV Infections, Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Cohort Studies, Major Articles and Brief Reports, Gene Frequency, Genotype, Humans, Immunology and Allergy, SNP, Allele frequency, Genetic Association Studies, Aged, Disease Resistance, Aged, 80 and over, Genetics, HCP5, virus diseases, Middle Aged, United States, Europe, Infectious Diseases, Genetic Loci, Steroid Hydroxylases, HIV-1, Female, Viral load
Abstract

In the past few years, several genomewide association studies (GWASs) have been conducted to identify host genetic variants involved in control of human immunodeficiency virus type 1 (HIV-1) load and in progression to AIDS [1–10]. Overall, these GWASs emphasized the major role of the HLA chromosome 6 region, particularly the HCP5/HLA-B*57 rs2395029 signal [1–3, 5, 8], and the CXCR6 gene region [7]. These GWASs focused on viral load and disease progression, but genetic correlates of the HIV-1 acquisition phenotype have met limited success: 2 recent GWASs conducted in Malawi reported no significant determinants of HIV infection [11, 12]. Looking for new host factors correlated to HIV susceptibility is critical because the only validated association to date is the 32 base-pair deletion in the CCR5 gene: only 1%–2% of Europeans are homozygous for this mutation and exhibit a near-complete protection against infection by HIV-1 R5 strains [13, 14]. To identify additional genetic factors that might contribute to HIV-1 acquisition, we performed a meta-analysis using GWAS genotypic data from 2 European AIDS progression cohorts, comparing each group of HIV-1–infected patients with uninfected controls of the same ancestry [8, 15]. Next, we replicated the association for the single-nucleotide polymorphism (SNP) showing the smallest P value in the European meta-analysis on 2 independent US cohorts of European ancestry.

Published
2012
Full Text
View/download PDF

10. Screening Low-Frequency SNPS From Genome-Wide Association Study Reveals a New Risk Allele for Progression to AIDS

Author

Philippe Froguel, Joshua T. Herbeck, Jean Louis Spadoni, Ping An, Sigrid Le Clerc, Olivier Delaneau, Jeremy J. Martinson, Matthieu Montes, Jan H. Veldink, François Schächter, Cheryl A. Winkler, Hanneke Schuitemaker, Leonard H. van den Berg, Safa Mellak, Taoufik Labib, Sophie Limou, Amu Therwath, James I. Mullins, Jean François Delfraissy, Lieng Taing, Daniëlle van Manen, Jean-François Zagury, Cédric Coulonges, Amsterdam institute for Infection and Immunity, and Experimental Immunology

Subjects
Adult, Male, Candidate gene, Linkage disequilibrium, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, HIV Long-Term Survivors, Humans, Genetic Predisposition to Disease, Pharmacology (medical), Alleles, Genetic association, Genetics, Acquired Immunodeficiency Syndrome, GTPase-Activating Proteins, Middle Aged, United States, Europe, Chromosome 17 (human), Minor allele frequency, Infectious Diseases, Immunology, Disease Progression, Female, Genome-Wide Association Study
Abstract

Background: Seven genome-wide association studies (GWAS) have been published in AIDS, and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide significance. Methods: We reanalyzed the data from 3 previously published GWAS, targeting specifically low-frequency SNPs (minor allele frequency

Published
2011
Full Text
View/download PDF

11. Multiple‐Cohort Genetic Association Study Reveals CXCR6 as a New Chemokine Receptor Involved in Long‐Term Nonprogression to AIDS

Author

Susan Buchbinder, Olivier Delaneau, Ivo Gut, Yves Levy, Matthieu Montes, Cheryl A. Winkler, Ping An, Gora Diop, James I. Mullins, Christine Rouzioux, Hanneke Schuitemaker, Philippe Froguel, Jérôme Estaquier, Jean-François Delfraissy, James J. Goedert, Amu Therwath, Jean-Daniel Lelièvre, Christian Dina, Sigrid Le Clerc, Angélique B. van 't Wout, Lieng Taing, Serge Hercberg, Sophie Limou, François Schächter, John P. Phair, Jean-François Zagury, Cédric Coulonges, Joshua T. Herbeck, Geoffrey S. Gottlieb, Sharyne M. Donfield, Daniëlle van Manen, Other departments, Amsterdam institute for Infection and Immunity, and Experimental Immunology

Subjects
Male, Virus genetics, Single-nucleotide polymorphism, Genome-wide association study, Biology, HIV Long-Term Survivors, Cohort Studies, Major Articles and Brief Reports, Humans, Immunology and Allergy, Genetic Association Studies, Receptors, CXCR6, Genetic association, Genetics, Acquired Immunodeficiency Syndrome, Polymorphism, Genetic, HCP5, Odds ratio, Immunity, Innate, Infectious Diseases, Immunology, HIV-1, Receptors, Virus, Receptors, Chemokine, Viral disease, Viral load
Abstract

a Background. The compilation of previous genomewide association studies of AIDS shows a major polymor- phism in the HCP5 gene associated with both control of the viral load and long-term nonprogression (LTNP) to AIDS. Methods. To look for genetic variants that affect LTNP without necessary control of the viral load, we reanalyzed the genomewide data of the unique LTNP Genomics of Resistance to Immunodeficiency Virus (GRIV) cohort by excluding "elite controller" patients, who were controlling the viral load at very low levels (!100 copies/mL). Results. The rs2234358 polymorphism in the CXCR6 gene was the strongest signal ( ; odds ratio, 7 P p 2.5 10 1.85) obtained for the genomewide association study comparing the 186 GRIV LTNPs who were not elite controllers with 697 uninfected control subjects. This association was replicated in 3 additional independent European studies, reaching genomewide significance of . This association with LTNP is independent of the 10 P p 9.7 10 combined CCR2-CCR5 locus and the HCP5 polymorphisms. Conclusions. The statistical significance, the replication, and the magnitude of the association demonstrate that CXCR6 is likely involved in the molecular etiology of AIDS and, in particular, in LTNP, emphasizing the power of extreme-phenotype cohorts. CXCR6 is a chemokine receptor that is known as a minor coreceptor in human immunodeficiency virus type 1 infection but could participate in disease progression through its role as a mediator of inflammation.

Published
2010
Full Text
View/download PDF

12. Epimerase activity of the human 11β-hydroxysteroid dehydrogenase type 1 on 7-hydroxylated C19-steroids

Author

Matthieu Montes, Henry Chermette, Olivier Hennebert, Alain Favre-Réguillon, Clotilde Ferroud, and Robert Morfin

Subjects
Cytochrome, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Cytochrome P450 Family 7, Dehydroepiandrosterone, Dehydrogenase, Epiandrosterone, Androsterone, Hydroxylation, Biochemistry, Cofactor, chemistry.chemical_compound, Endocrinology, 11β-hydroxysteroid dehydrogenase type 1, Catalytic Domain, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Humans, Molecular Biology, Molecular Structure, biology, Chemistry, Active site, Cell Biology, Androstane-3,17-diol, Steroid Hydroxylases, biology.protein, Molecular Medicine, Steroids, Oxidation-Reduction, hormones, hormone substitutes, and hormone antagonists
Abstract

Cytochrome P4507B1 7alpha-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5alpha-androstane-3beta,17beta-diol (Adiol). 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts 7alpha- and 7beta-forms. Whether the interconversion proceeds through oxido-reductive steps or epimerase activity was investigated. Experiments using [(3)H]-labelled 7beta-hydroxy-DHEA, 7beta-hydroxy-EpiA and 7beta-hydroxy-Adiol showed the (3)H-label to accumulate in the 7-oxo-DHEA trap but not in 7-oxo-EpiA or 7-oxo-Adiol traps. Computed models of 7-oxygenated steroids docked in the active site of 11beta-HSD1 either in a flipped or turned form relative to cortisone and cortisol. 7-Oxo-steroid reduction in 7alpha- or 7beta-hydroxylated derivatives resulted from either turned or flipped forms. 11beta-HSD1 incubation in H(2)(18)O medium with each 7-hydroxysteroid did not incorporate (18)O in 7-hydroxylated derivatives of EpiA and Adiol independently of the cofactor used. Thus oxido-reductive steps apply for the interconversion of 7alpha- and 7beta-hydroxy-DHEA through 7-oxo-DHEA. Epimerization may proceed on the 7-hydroxylated derivatives of EpiA and Adiol through a mechanism involving the cofactor and Ser(170). The physiopathological importance of this epimerization process is related to 7beta-hydroxy-EpiA production and its effects in triggering the resolution of inflammation.

Published
2009
Full Text
View/download PDF

13. Evidence after imputation for a role of MICA variants in nonprogression and elite control of HIV type 1 infection

Author

Sigrid Le Clerc, Vincent Laville, Taoufik Labib, Jean-Louis Spadoni, François Schächter, Jean-François Zagury, Cédric Coulonges, Josselin Noirel, Sophie Caillat-Zucman, Damien Ulveling, Olivier Delaneau, and Matthieu Montes

Subjects
Adult, Male, Linkage disequilibrium, RNA, Untranslated, Genome-wide association study, Single-nucleotide polymorphism, HIV Infections, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Cohort Studies, Major Histocompatibility Complex, Young Adult, Immunology and Allergy, Humans, 1000 Genomes Project, Genetic Association Studies, Genetic association, Disease Resistance, Genetics, HCP5, Haplotype, Histocompatibility Antigens Class I, Middle Aged, Virology, Infectious Diseases, Haplotypes, HIV-1, Female, RNA, Long Noncoding, Imputation (genetics)
Abstract

Past genome-wide association studies (GWAS) involving individuals with AIDS have mainly identified associations in the HLA region. Using the latest software, we imputed 7 million single-nucleotide polymorphisms (SNPs)/indels of the 1000 Genomes Project from the GWAS-determined genotypes of individuals in the Genomics of Resistance to Immunodeficiency Virus AIDS nonprogression cohort and compared them with those of control cohorts. The strongest signals were in MICA, the gene encoding major histocompatibility class I polypeptide-related sequence A (P = 3.31 × 10(-12)), with a particular exonic deletion (P = 1.59 × 10(-8)) in full linkage disequilibrium with the reference HCP5 rs2395029 SNP. Haplotype analysis also revealed an additive effect between HLA-C, HLA-B, and MICA variants. These data suggest a role for MICA in progression and elite control of human immunodeficiency virus type 1 infection.

Published
2014

14. Targeting IL-6 by both passive or active immunization strategies prevents bleomycin-induced skin fibrosis

Author

Maxime Fréchet, Yannick Allanore, Jérôme Avouac, Lucille Desallais, Rojo Ratsimandresy, Hadley Mouhsine, Hervé Do, Muriel Elhai, Matthieu Montes, Jean-François Zagury, EQUIPE GÉNOMIQUE, BIOINFORMATIQUE ET PATHOLOGIES DU SYSTÈME IMMUNITAIRE, Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Service de rhumatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Peptinov, Peptinov SAS, and LD was funded by a fellowship from Direction Générale de l ' Armement, and the work was funded in part by Conservatoire National des Arts et Métiers.

Subjects
Adult, Male, medicine.medical_treatment, Immunology, Enzyme-Linked Immunosorbent Assay, Active immunization, Bleomycin, Skin Diseases, chemistry.chemical_compound, Hydroxyproline, Mice, Rheumatology, Fibrosis, Medicine, Immunology and Allergy, Animals, Humans, Interleukin 6, Aged, Antibiotics, Antineoplastic, Scleroderma, Systemic, biology, integumentary system, business.industry, Interleukin-6, Antibodies, Monoclonal, Middle Aged, medicine.disease, Immunohistochemistry, Disease Models, Animal, Cytokine, chemistry, Monoclonal, biology.protein, Female, Immunization, Antibody, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Research Article
Abstract

International audience; INTRODUCTION: Interleukin-6 (IL-6) is a pleiotropic cytokine for which preliminary data have suggested that it might contribute to systemic sclerosis (SSc). Our aims were to investigate, firstly, IL-6 expression in patients with SSc and, secondly, the efficacy of both passive and active immunization against IL-6 to reduce skin fibrosis in complementary mouse models of SSc. METHODS: Human serum levels and skin expression of IL-6 were determined by enzyme-linked immunosorbent assay and immunohistochemistry, respectively. We first evaluated the antifibrotic properties of the monoclonal anti-IL-6R antibody, MR16-1, in the bleomycin-induced dermal fibrosis mouse model, reflecting early and inflammatory stages of SSc. Then, we assessed the efficacy of MR16-1 in tight skin-1 (Tsk-1) mice, an inflammation-independent model of skin fibrosis. Additionally, we have developed an innovative strategy using an anti-IL-6 peptide-based active immunization. Infiltrating leukocytes, T cells, and B cells were quantified, and IL-6 levels were measured in the serum and lesional skin of mice after passive or active immunization. RESULTS: Serum and skin levels of IL-6 were significantly increased in patients with early SSc. Treatment with MR16-1 led in the bleomycin mouse model to a 25% (P = 0.02) and 30% (P = 0.007) reduction of dermal thickness and hydroxyproline content, respectively. MR16-1 demonstrated no efficacy in Tsk-1 mice. Thereafter, mice were immunized against a small peptide derived from murine IL-6 and this strategy led in the bleomycin model to a 20% (P = 0.02) and 25% (P = 0.005) decrease of dermal thickness and hydroxyproline content, respectively. Passive and active immunization led to decreased T-cell infiltration in the lesional skin of mice challenged with bleomycin. Upon bleomycin injections, serum and skin IL-6 levels were increased after treatment with MR16-1 and were significantly reduced after anti-IL-6 active immunization. CONCLUSIONS: Our results support the relevance of targeting IL-6 in patients with early SSc since IL-6 is overexpressed in early stages of the disease. Targeting IL-6 by both passive and active immunization strategies prevented the development of bleomycin-induced dermal fibrosis in mice. Our results highlight the therapeutic potential of active immunization against IL-6, which is a seductive alternative to passive immunization.

Published
2013
Full Text
View/download PDF

15. Novel Organic Proteasome Inhibitors Identified by Virtual and in Vitro Screening

Author

Michèle Reboud-Ravaux, Matthieu Montes, Bruno O. Villoutreix, Lixian Qin, Joëlle Vidal, Xavier Maréchal, Michelle Bouvier-Durand, Emilie Genin, Nicolas Basse, Enzymologie Moléculaire et Fonctionnelle, Université Pierre et Marie Curie - Paris 6 (UPMC), Pharmacochimie Moléculaire et Cellulaire (PMC - UMR_S 648), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Molécules Thérapeutiques in silico (MTI), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Lab Animal Sciences, China Academy of Medical Sciences, Chimie et Photonique Moléculaires (CPM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Proteines Biochimie Structurale et Fonctionnelle (FRE 2852), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Pharmacochimie Moléculaire et Cellulaire ( PMC - UMR_S 648 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Molécules Thérapeutique in silico, Recherche de molécules à visée thérapeutique par approches In Silico ( MTI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Chimie et Photonique Moléculaires ( CPM ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Proteines Biochimie Structurale et Fonctionnelle ( FRE 2852 ), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
Models, Molecular, Databases, Factual, Antineoplastic Agents, Crystallography, X-Ray, 01 natural sciences, Piperazines, Cell Line, Sulfone, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, [ CHIM.ORGA ] Chemical Sciences/Organic chemistry, Drug Discovery, medicine, Animals, Humans, Protease Inhibitors, Sulfones, Piperazine, Cell Proliferation, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Virtual screening, Molecular Structure, biology, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Stereoisomerism, Ligand (biochemistry), In vitro, 3. Good health, 0104 chemical sciences, Enzyme, Proteasome, Biochemistry, Enzyme inhibitor, Proteasome inhibitor, biology.protein, Molecular Medicine, Rabbits, Drug Screening Assays, Antitumor, Proteasome Inhibitors, HeLa Cells, medicine.drug
Abstract

International audience; Proteasome inhibition is a promising strategy for treating cancers. Herein, we report the discovery of novel drug-like inhibitors of mammalian proteasome 20S using a multistep structure-based virtual ligand screening strategy. Sulfone- or piperazine-containing hits essentially belong to the under-represented class of noncovalent and nonpeptidic proteasome inhibitors. Several of our compounds act in the micromolar range and are cytotoxic on human tumoral cell lines. Optimization of these molecules could lead to better anticancer therapy.

Published
2009
Full Text
View/download PDF

16. Genomewide Association Study of a Rapid Progression Cohort Identifies New Susceptibility Alleles for AIDS (ANRS Genomewide Association Study 03)

Author

François Schächter, Christiane Deveau, Jean-Daniel Lelièvre, Olivier Delaneau, Matthieu Montes, Serge Hercberg, Jean-François Zagury, Cédric Coulonges, Jean-Louis Spadoni, Hélène Guillemain, Wassila Carpentier, Philippe Froguel, Christian Dina, Lieng Taing, Amu Therwath, Jean-François Delfraissy, Sigrid Le Clerc, Robert Sladek, Ivo Gut, Yves Levy, Rojo Ratsimandresy, Taoufik Labib, Sophie Limou, Fumihiko Matsuda, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Chaire de Bioinformatique, Conservatoire National des Arts et Métiers [CNAM] (CNAM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut de biologie de Lille - UMS 3702 (IBL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Etudes génomiques trans-ethniques des maladies multifactorielles, Kyoto University [Kyoto]-Institut National de la Santé et de la Recherche Médicale (INSERM), Imperial College London, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Paris 13 (UP13), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Kyoto University-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, and Gestionnaire, Hal Sorbonne Université

Subjects
Linkage disequilibrium, Genotype, [SDV]Life Sciences [q-bio], Genome-wide association study, Single-nucleotide polymorphism, Disease, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, HIV Seropositivity, Immunology and Allergy, Humans, Genetic Predisposition to Disease, Allele, Alleles, 030304 developmental biology, Genetics, 0303 health sciences, Acquired Immunodeficiency Syndrome, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Genome, Human, Haplotype, Case-control study, Odds ratio, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Phenotype, Gene Expression Regulation, 030220 oncology & carcinogenesis, Case-Control Studies, Disease Progression, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

BACKGROUND Previous genomewide association studies (GWASs) of AIDS have targeted end points based on the control of viral load and disease nonprogression. The discovery of genetic factors that predispose individuals to rapid progression to AIDS should also reveal new insights into the molecular etiology of the pathology. METHODS We undertook a case-control GWAS of a unique cohort of 85 human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced rapid disease progression, using Illumina HumanHap300 BeadChips. The case group was compared with a control group of 1352 individuals for the 291,119 autosomal single-nucleotide polymorphisms (SNPs) passing the quality control tests, using the false-discovery rate (FDR) statistical method for multitest correction. RESULTS Novel associations with rapid progression (FDR, < or = 25%) were identified for PRMT6 (P = 6.1 x 10(-7); odds ratio [OR], 0.24), SOX5 (P = 1.8 x 10(-6); OR, 0.45), RXRG (P = 3.9 x 10(-6); OR, 3.29), and TGFBRAP1 (P = 7 x 10(-6); OR, 0.34). The haplotype analysis identified exonic and promoter SNPs potentially important for PRMT6 and TGFBRAP1 function. CONCLUSIONS The statistical and biological relevance of these associations and their high ORs underscore the power of extreme phenotypes for GWASs, even with a modest sample size. These genetic results emphasize the role of the transforming growth factor beta pathway in the pathogenesis of HIV-1 disease. Finally, the wealth of information provided by this study should help unravel new diagnostic and therapeutic targets.

Published
2009
Full Text
View/download PDF

17. Genomewide Association Study of an AIDS‐Nonprogression Cohort Emphasizes the Role Played by HLA Genes (ANRS Genomewide Association Study 02)

Author

Olivier Delaneau, Philippe Froguel, Matthieu Montes, Yves Levy, Rojo Ratsimandresy, Christine Rouzioux, Sigrid Le Clerc, Ioannis Theodorou, François Schächter, Laurence Meyer, Philippe Broët, Amu Therwath, Christian Dina, Robert Sladek, Christiane Deveau, Ivo Gut, Cyril Dalmasso, Jean Louis Spadoni, Taoufik Labib, Sophie Limou, Wassila Carpentier, Jean-Daniel Lelièvre, Fumihiko Matsuda, Serge Hercberg, Patrice Debré, Jean François Delfraissy, Lieng Taing, Jean-François Zagury, Cédric Coulonges, Chaire de Bioinformatique, Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut de biologie de Lille - UMS 3702 (IBL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), McGill University and Genome Quebec Innovation Centre, Université Paris Diderot - Paris 7 (UPD7), Etudes génomiques trans-ethniques des maladies multifactorielles, Kyoto University-Institut National de la Santé et de la Recherche Médicale (INSERM), Imperial College London, ANRS France Recherche Nord & sud Sida-hiv hépatites, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Paris 13 (UP13), Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS), Innovation 2007 program of the Conservatoire National des Arts et Métiers, AIDS Cancer Vaccine Development Foundation, Neovacs SA, Vaxconsulting. S.L. benefits from a fellowship from the French Ministry of Education, Technology, and Research, and S.L.C. benefits from a fellowship from ANRS, We are grateful to all the patients and medical staff who have kindly collaborated with the GRIV project., The ANRS Genomic Group is composed of Prof. Jean-François Delfraissy (Agence Nationale de Recherche sur le SIDA et les Hépatites Virales, Paris), Dr. Laurence Meyer (Hôpital Kremlin- Bicêtre, France), Prof. Philippe Broët (Hôpital Kremlin-Bicêtre, France), Dr. Cyril Dalmasso (Hôpital Kremlin-Bicêtre, France), Dr. Wassila Carpentier (Hôpital La Salpêtrière, Paris), Prof. Patrice Debre' (Hôpital La Salpêtrière, Paris), Dr. Ioannis Théodorou (Hôpital La Salpêtriére, Paris), Prof. Christine Rouzioux (Hôpital Necker, Paris), Cédric Coulonges (Conservatoire National des Arts et Métiers, Paris), Sigrid Le Clerc (Conservatoire National des Arts et Métiers, Paris), Sophie Limou (Conservatoire National des Arts et Métiers, Paris), and Prof. Jean- Françis Zagury (Conservatoire National des Arts et Métiers, Paris), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Kyoto University [Kyoto]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, and Gestionnaire, Hal Sorbonne Université

Subjects
Linkage disequilibrium, Genotype, MESH: HIV-1, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Biology, MESH: Acquired Immunodeficiency Syndrome/genetics, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Cohort Studies, Major Histocompatibility Complex, MESH: Genotype, 03 medical and health sciences, 0302 clinical medicine, MESH: Genome, Human, HLA Antigens, HIV Seropositivity, HLA-B Antigens, Humans, Immunology and Allergy, SNP, MESH: HLA Antigens/genetics, MESH: Major Histocompatibility Complex/genetics, MESH: HIV Seropositivity/genetics, MESH: Cohort Studies, 030304 developmental biology, Genetics, Acquired Immunodeficiency Syndrome, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Humans, Genome, Human, MESH: Polymorphism, Single Nucleotide, HCP5, Haplotype, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, MESH: Linkage Disequilibrium, Immunology, Disease Progression, HIV-1, MESH: Disease Progression, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

To elucidate the genetic factors predisposing to AIDS progression, we analyzed a unique cohort of 275 human immunodeficiency virus (HIV) type 1-seropositive nonprogressor patients in relation to a control group of 1352 seronegative individuals in a genomewide association study (GWAS). The strongest association was obtained for HCP5 rs2395029 (P = 6.79 × 10 −10 ; odds ratio, 3.47) andwaspossibly linkedto aneffect of sex. Interestingly, this single-nucleotide polymorphism (SNP) was in high linkage disequilibrium with HLA-B, MICB, TNF, and several other HLA locus SNPs and haplotypes. A meta-analysis of our genomic data combined with data from the previously conducted Euro-CHAVI (Center for HIV/AIDS Vaccine Immunology) GWAS confirmed the HCP5 signal (P = 3.02 × 10 −19 ) and identified several new associations, all of them involving HLA genes: MICB, TNF, RDBP, BAT1-5, PSORS1C1, and HLA-C. Finally, stratification by HCP5 rs2395029 genotypes emphasized an independent role for ZNRD1, also in the HLA locus, and this finding was confirmed by experimental data. The present study, the first GWAS of HIV-1 nonprogressors, underscores the potential for some HLA genes to control disease progression soon after infection.

Published
2009
Full Text
View/download PDF

18. Steroid substrate-induced epimerase mechanism in the active site of the human 11&946;-hydroxysteroid dehydrogenase type 1

Author

Henry Chermette, Alain Favre-Réguillon, Olivier Hennebert, Robert Morfin, Clotilde Ferroud, and Matthieu Montes

Subjects
biology, Chemistry, Stereochemistry, medicine.medical_treatment, Active site, Alpha (ethology), Dehydrogenase, Epiandrosterone, Cofactor, Steroid, 11β-hydroxysteroid dehydrogenase type 1, biology.protein, medicine, General Materials Science, Beta (finance), hormones, hormone substitutes, and hormone antagonists
Abstract

Cytochrome P4507B1 7[alpha]-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5[alpha]-androstane-3[beta],17[beta]-diol (Adiol). 11[beta]-Hydroxysteroid dehydrogenase type 1 (11[beta]-HSD1) interconverts 7[alpha]- and 7[beta]- forms. Whether the inter-conversion proceeds through oxido-reductive steps or epimerase activity is investigated. Experiments using ^3^H-labeled 7[beta]-hydroxy-DHEA, 7[beta]-hydroxy-EpiA and 7[beta]-hydroxy-Adiol show the ^3^H-label to accumulate in 7-oxo-DHEA trap but neither in 7-oxo-EpiA nor 7-oxo-Adiol traps. Computed models of 7-oxygenated steroids dock in the active site of 11[beta]-HSD1 either in a flipped or turned form relative to cortisone and cortisol. 7-Oxo-steroid reduction in 7[alpha]- or 7[beta]-hydroxylated derivatives results from either turned or flipped forms. 11[beta]-HSD1 incubation in H~2~^18^O medium with each 7-hydroxysteroid did not incorporate ^18^O in 7-hydroxylated derivatives of EpiA and Adiol independently of the cofactor used. Thus oxido-reductive steps apply for the interconversion of 7[alpha]- and 7[beta]-hydroxy-DHEA through 7-oxo-DHEA. Epimerisation may proceed on the 7-hydroxylated derivatives of EpiA and Adiol through a mechanism involving the cofactor and Ser170.

Published
2008
Full Text
View/download PDF

19. FAF-Drugs: free ADME/tox filtering of compound collections

Author

Stephanie Violas, Pierre Tufféry, Bruno O. Villoutreix, Matthieu Montes, Maria A. Miteva, David Gomez, Villoutreix, Bruno, Pharmacochimie Moléculaire et Cellulaire (PMC - UMR_S 648), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bioinformatique génomique et moléculaire ((U 726)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inserm, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris Descartes - Paris 5 (UPD5), Bioinformatique génomique et moléculaire, and Université Paris Diderot - Paris 7 (UPD7) - Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Preparation stage, Drug-Related Side Effects and Adverse Reactions, Simplified molecular-input line-entry system, drug design, In silico, Computational biology, Biology, Bioinformatics, 01 natural sciences, chemoinformatics, Article, 03 medical and health sciences, User-Computer Interface, Genetics, Pharmacokinetics, 030304 developmental biology, ADME, 0303 health sciences, Filtering rules, Internet, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Drug discovery, computer.file_format, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Adme tox, 0104 chemical sciences, 3. Good health, [SDV.TOX] Life Sciences [q-bio]/Toxicology, 010404 medicinal & biomolecular chemistry, Pharmaceutical Preparations, Cheminformatics, [SDV.TOX]Life Sciences [q-bio]/Toxicology, computer, Software
Abstract

In silico screening based on the structures of the ligands or of the receptors has become an essential tool to facilitate the drug discovery process but compound collections are needed to carry out such in silico experiments. It has been recognized that absorption, distribution, metabolism, excretion and toxicity (ADME/tox) are key properties that need to be considered early on, even during the database preparation stage. FAF-Drugs is an online service based on Frowns (a chemoinformatics toolkit) that allows users to process their own compound collections via simple ADME/Tox filtering rules such as molecular weight, polar surface area, logP or number of rotatable bonds. SMILES (Simplified Molecular Input Line Entry System), CANSMILES (canonical smiles) or SDF (structure data file) files are required as input and molecules that pass or do not pass the filters are sent back in CANSMILES format. This service should thus help scientists engaging in drug discovery campaigns. Other utilities and several compound collections suitable for in silico screening are available at our site. FAF-Drugs can be accessed at http://bioserv.rpbs.jussieu.fr/FAFDrugs.html.

Published
2006

20. Design, synthesis, and biological evaluation of novel naphthoquinone derivatives with CDC25 phosphatase inhibitory activity

Author

Matthieu Montes, Emmanuelle Braud, Marie-Priscille Brun, Delphine Angotti, Bernard Ducommun, Nohad Gresh, Christiane Garbay, Maria A. Miteva, Odile Mondesert, Muriel Quaranta, Pharmacochimie Moléculaire et Cellulaire (PMC - UMR_S 648), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie Moléculaire et Cellulaire ( PMC - UMR_S 648 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération ( LBCMCP ), Université Toulouse III - Paul Sabatier ( UPS ), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique ( CNRS )

Subjects
Models, Molecular, MESH : Drug Design, MESH : Hela Cells, MESH : cdc25 Phosphatases, Clinical Biochemistry, Pharmaceutical Science, Apoptosis, Cell Cycle Proteins, MESH: Cell Cycle, MESH: Drug Design, 01 natural sciences, Biochemistry, HeLa, MESH: Recombinant Proteins, chemistry.chemical_compound, MESH : Cell Cycle Proteins, MESH: cdc25 Phosphatases, Drug Discovery, Enzyme Inhibitors, MESH : Vitamin K 3, MESH: Naphthoquinones, MESH: Inhibitory Concentration 50, 0303 health sciences, biology, Cell Cycle, Vitamin K 3, Biological activity, Cell cycle, MESH: Vitamin K 3, Naphthoquinone, Recombinant Proteins, 3. Good health, MESH : Antineoplastic Agents, MESH : Inhibitory Concentration 50, MESH: Enzyme Inhibitors, Molecular Medicine, MESH: Models, Molecular, CDC25A, MESH: Cell Line, Tumor, MESH : Models, Molecular, MESH : Recombinant Proteins, Cdc25, Antineoplastic Agents, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, Inhibitory Concentration 50, MESH: Cell Cycle Proteins, Cyclin-dependent kinase, Cell Line, Tumor, MESH : Cell Cycle, Humans, cdc25 Phosphatases, Molecular Biology, 030304 developmental biology, MESH : Enzyme Inhibitors, MESH: Humans, MESH : Cell Line, Tumor, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, 010405 organic chemistry, Cell growth, MESH : Naphthoquinones, MESH: Apoptosis, MESH : Humans, Organic Chemistry, biology.organism_classification, 0104 chemical sciences, MESH: Hela Cells, chemistry, Drug Design, biology.protein, MESH: Antineoplastic Agents, MESH : Apoptosis, HeLa Cells, Naphthoquinones
Abstract

CDC25 dual-specificity phosphatases are essential key regulators of eukaryotic cell cycle progression and the CDC25A and B isoforms are over-expressed in different tumors and related cancer cell lines. CDC25s are now considered to be interesting targets in the search for novel anticancer agents. We describe new compounds derived from vitamin K3 that inhibit CDC25B activity with IC50 values in the low micromolar range. These naphthoquinone derivatives also display antiproliferative activity on HeLa cells as expected for CDC25 inhibitors and inhibit cell growth in a clonogenic assay at submicromolar concentrations. They increase inhibitory tyrosine 15 phosphorylation of CDK and induce the cleavage of PARP, a hallmark of apoptosis.

Published
2005
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results