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68 results on '"Munoz-Torrero, Diego"'

58. List of Contributors

Author

Agnetta, Luca, Bolognesi, Maria Laura, Bongarzone, Salvatore, Bottegoni, Giovanni, Carreiras, María do Carmo, Cavalli, Andrea, Chibale, Kelly, Decker, Michael, Dolles, Dominik, Gilmer, John F., He, Liu, Huang, Guozheng, Ismaili, Lhassane, Marco-Contelles, José, Muñoz-Torrero, Diego, Njogu, Peter Mbugua, Okombo, John, Prati, Federica, Romero, Alejandro, Saathoff, John M., Uliassi, Elisa, Zhang, Shijun, and Zhao, Qingjie

Published
2017
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59. Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: conformational analysis and binding mode of multisite inhibitors

Author

Di Pietro, Ornella, Juarez-Jimenez, Jordi, Munoz-Torrero, Diego, Laughton, Charles A., Luque, F. Javier, Di Pietro, Ornella, Juarez-Jimenez, Jordi, Munoz-Torrero, Diego, Laughton, Charles A., and Luque, F. Javier

Abstract

The critical role of BACE-1 in the formation of neurotoxic ß-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimer’s disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challeng- ing. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragments—huprine and rhein— that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8–14, 154–169 and 307–318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable “floppy” pocket would enable the bind- ing of multisite inhibitors targeting both catalytic and secondary sites. Molecular dynamics simulations of BACE-1 bound to huprine-rhein hybrid compounds support the feasibility of this hypothesis. The results provide a basis to explain the high inhibitory potency of the two enantiomeric forms of 1, together with the large dependence on the length of the oligo- methylenic linker. Furthermore, the multisite hypothesis has allowed us to rationalize the inhibitory potency of a series of tacrine-chromene hybrid compounds, specifically regarding the apparent lack of sensitivity of the inhibition constant to the chemical modifications intro- duced in the chromene unit. Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors.

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67. Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis

Author

Israel Silman, Ludovic Jean, Pierre-Yves Renard, Belén Pérez, Diego Muñoz-Torrero, Nicolas Coquelle, Jacques-Philippe Colletier, Monika Cieslikiewicz-Bouet, Carles Galdeano, Manuela Bartolini, M.V. Clos, Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy and Food Sciences, Institut de biologie structurale ( IBS - UMR 5075 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Chimie Organique et Bioorganique : Reactivité et Analyse ( COBRA ), Centre National de la Recherche Scientifique ( CNRS ) -Institut de Chimie Organique Fine ( IRCOF ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut national des sciences appliquées Rouen Normandie ( INSA Rouen Normandie ), Normandie Université ( NU ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratory of Bioinorganic Chemistry, Department of Pharmacy and Biotechnology, University of Bologna, Viale Giuseppe Fanin, 40, 40127 Bologna, Italy, Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona [Barcelona] ( UAB ), Department of Neurobiology, Weizmann Institute of Science, Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Galdeano, Carle, Coquelle, Nicola, Cieslikiewicz-Bouet, Monika, Bartolini, Manuela, Pérez, Belén, Victòria Clos, M., Silman, Israel, Jean, Ludovic, Colletier, Jacques-Philippe, Renard, Pierre-Yve, Munoz-Torrero, Diego, Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Universitat Autònoma de Barcelona (UAB), Weizmann Institute of Science [Rehovot, Israël], Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Universitat de Barcelona

Subjects
0301 basic medicine, Models, Molecular, Malalties neuromusculars, Pharmaceutical Science, quinolinium compounds, Pharmacology, Analytical Chemistry, copper-catalyzed azide-alkyne cycloaddition, chemistry.chemical_compound, Drug Discovery, structural biology, Butyrylcholinesterase, media_common, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Molecular Structure, Chemistry, Acetilcolinesterasa, Acetylcholinesterase, 3. Good health, quinolinium compound, Neuromuscular diseases, Pyridostigmine, Chemistry (miscellaneous), acetylcholinesterase inhibitors, Tacrine, click chemistry, language, Aminoquinolines, Molecular Medicine, butyrylcholinesterase inhibitors, medicine.drug, Drug, Aché, media_common.quotation_subject, Triazole, Down-Regulation, GPI-Linked Proteins, Heterocyclic Compounds, 4 or More Rings, Article, lcsh:QD241-441, 03 medical and health sciences, Structure-Activity Relationship, lcsh:Organic chemistry, Myasthenia Gravis, medicine, Humans, Physical and Theoretical Chemistry, triazoles, Aminoacridines, Organic Chemistry, Triazoles, medicine.disease, Myasthenia gravis, language.human_language, triazole, 030104 developmental biology, Cholinesterase Inhibitors, butyrylcholinesterase inhibitor, acetylcholinesterase inhibitor, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract

Altres ajuts: FA/AAP-2013-65-101349 Altres ajuts: ANR/ANR-12-BS07-0008-01 Altres ajuts: ANR/ANR-11-LABX-0029 Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis.

Published
2018
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68. Rhein-Huprine Derivatives Reduce Cognitive Impairment, Synaptic Failure and Amyloid Pathology in AβPPswe/PS-1 Mice of Different Ages.

Author

Serrano FG, Tapia-Rojas C, Carvajal FJ, Cisternas P, Viayna E, Sola I, Munoz-Torrero D, and Inestrosa NC

Subjects
Aging drug effects, Aging metabolism, Aging pathology, Alzheimer Disease metabolism, Alzheimer Disease pathology, Alzheimer Disease psychology, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Animals, Cognitive Dysfunction drug therapy, Cognitive Dysfunction metabolism, Cognitive Dysfunction pathology, Disease Models, Animal, Humans, Inflammation drug therapy, Inflammation metabolism, Inflammation pathology, Long-Term Potentiation drug effects, Long-Term Potentiation physiology, Mice, Transgenic, Peptide Fragments metabolism, Phosphorylation drug effects, Plaque, Amyloid drug therapy, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, Presenilin-1 genetics, Presenilin-1 metabolism, Synapses drug effects, Synapses metabolism, Synapses pathology, tau Proteins metabolism, Alzheimer Disease drug therapy, Aminoquinolines pharmacology, Anthraquinones pharmacology, Neuroprotective Agents pharmacology, Nootropic Agents pharmacology
Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) peptide plays a key role in synaptic impairment and memory decline associated with neuronal dysfunction and intra-neuronal accumulation of hyperphosphorylated tau protein. Two novel enantiopure rhein-huprine hybrids ((+)-1 and (-)-1) exhibit potent inhibitory effects against human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE-1 and both Aβ and tau antiaggregation activity in vitro and reduction on the amyloid precursor protein (APP) processing in vivo. Interestingly, in this work, we observed beneficial effects with both (+)- and (-)-1 in the reversion of the neuropathology presented in the AβPPswe/PS-1 Alzheimer´s model, including a reduction in the Aβ levels, tau phosphorylation and memory impairment with both treatments. Also, in young transgenic mice that present early symptoms of synaptic failure and memory loss, we found a protection of cognitive functions, including long-term potentiation (LTP) and a reduction of the neuro-inflammation by both (+)- and (-)-1. Furthermore, animals with an advanced disease (11month-old) present an exacerbate neurodegeneration that is reversed only with the dextrorotatory enantiomer. These studies indicated that rhein-huprine derivatives with multiple properties might have interesting therapeutic potential for AD.

Published
2016
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