title: Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1.
abstract: Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of the tissue type and urokinase type plasminogen activators. High levels of PAI-1 are correlated with an increased risk of thrombotic events and several other pathologies. Despite several compounds with in vitro activity being developed, none of them are currently in clinical use. In this study, we evaluated a novel PAI-1 inhibitor, annonacinone, a natural product from the Annonaceous acetogenins group. Annonacinone was identified in a chromogenic screening assay and was more potent than tiplaxtinin. Annonacinone showed high potency ex vivo on thromboelastography and was able to potentiate the thrombolytic effect of tPA in vivo in a murine model. SDS-PAGE showed that annonacinone inhibited formation of PAI-1/tPA complex via enhancement of the substrate pathway. Mutagenesis and molecular dynamics allowed us to identify annonacinone binding site close to helix D and E and β-sheets 2A.
authors.affiliation: Université Paris-Sud, INSERM UMR-S1176, 94276 Le Kremlin-Bicêtre, France.|Servier Research Institute, 11 rue des Moulineaux 92150 Suresnes, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pautus
authors.affiliation: Université Paris-Sud, BioCIS, 5 rue Jean-Baptiste Clément 92290 Châtenay-Malabry, France.
authors.forename: Mouad
authors.initials: M
authors.lastname: Alami
authors.affiliation: Université Paris-Sud, INSERM UMR-S1176, 94276 Le Kremlin-Bicêtre, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Adam
authors.affiliation: Université Paris-Sud, BioCIS, 5 rue Jean-Baptiste Clément 92290 Châtenay-Malabry, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bernadat
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.affiliation: Université Paris-Sud, INSERM UMR-S1176, 94276 Le Kremlin-Bicêtre, France.
authors.forename: Allan
authors.initials: A
authors.lastname: De Carvalho
authors.affiliation: Servier Research Institute, 11 rue des Moulineaux 92150 Suresnes, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Ferry
authors.affiliation: Servier Research Institute, 11 rue des Moulineaux 92150 Suresnes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Rupin
authors.affiliation: Université Paris-Sud, BioCIS, 5 rue Jean-Baptiste Clément 92290 Châtenay-Malabry, France.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Hamze
authors.affiliation: Laboratoire de Pharmacognosie, BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, UFR Pharmacie, 5 rue Jean-Baptiste Clément, 92290, Châtenay-Malabry, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Champy
authors.affiliation: Laboratoire de Pharmacognosie, BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, UFR Pharmacie, 5 rue Jean-Baptiste Clément, 92290, Châtenay-Malabry, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Bonneau
authors.affiliation: Servier Research Institute, 11 rue des Moulineaux 92150 Suresnes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gloanec
authors.affiliation: Servier Research Institute, 11 rue des Moulineaux 92150 Suresnes, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Peglion
authors.affiliation: Université Paris-Sud, BioCIS, 5 rue Jean-Baptiste Clément 92290 Châtenay-Malabry, France.
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Brion
authors.affiliation: Université Paris-Sud, INSERM UMR-S1176, 94276 Le Kremlin-Bicêtre, France.
authors.forename: Elsa P
authors.initials: EP
authors.lastname: Bianchini
authors.affiliation: Université Paris-Sud, INSERM UMR-S1176, 94276 Le Kremlin-Bicêtre, France.|AP-HP, Hôpital Necker, Service d'Hématologie Biologique, 75015 Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Borgel
mesh_terms: D015107:4-Butyrolactone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007210:Indoleacetic Acids / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D023421:Models, Animal; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D013916:Thrombelastography
chemical_list: D005343:Fibrinolytic Agents; D007210:Indoleacetic Acids; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C570175:annonacinone; C488103:tiplaxtinin; D015107:4-Butyrolactone