Identification of an in vivo orally active dual-binding protein-protein interaction inhibitor targeting TNFα through combined in silico/in vitro/in vivo screening
| Autor: | 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 |
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| Přispěvatelé: | 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), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2017 |
| Předmět: |
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 |
| Zdroj: | Scientific Reports Scientific Reports, Nature Publishing Group, 2017, 7 (1), pp.3424. ⟨10.1038/s41598-017-03427-z⟩ Scientific Reports, Vol 7, Iss 1, Pp 1-10 (2017) Scientific Reports, 2017, 7 (1), pp.3424. ⟨10.1038/s41598-017-03427-z⟩ Scientific Reports, Nature Publishing Group, 2017, 7 (1), pp.3424. 〈10.1038/s41598-017-03427-z〉 |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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