Monoaryl derivatives as transthyretin fibril formation inhibitors: Design,synthesis, biological evaluation and structural analysis |
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| Affiliation: | 1. Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy;2. Synchrotron SOLEIL, L’Orme des Merisiers, Saint-Aubin, BP 48, 91192 Gif-sur-Yvette, France;3. Université Paris-Saclay, CNRS, BioCIS, rue Jean-Baptiste Clément 5, 92290 Châtenay-Malabry, France;4. Université Paris Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SIMoS, 91191 Gif-sur-Yvette, France;5. Research Center “E. Piaggio”, Università di Pisa, Pisa 56122, Italy;6. Department of Earth Sciences, University of Pisa, Via Santa Maria 53-55, 56100 Pisa, Italy;1. Department of Chemistry, The University of Hong Kong, Hong Kong, China;2. Department of Infectious Diseases and Public Health, The City University of Hong Kong, PR China;1. Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1, Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka 808-0135, Japan;2. University of Occupational and Environmental Health, 1-1 Isegaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan;1. Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain;2. Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain;3. Área de Farmacología, Nutrición y Bromatología, Unidad Asociada al IQM y al CIAL (CSIC), Departamento de C.C. Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. Atenas s/n, 28922 Alcorcón, Spain;4. U.G.C de Metabolismo Óseo, RedinREN del ISC III, Hospital Universitario Central de Asturias, Instituto de Investigaciones Sanitarias del Principado de Asturias, Edificio FINBA, Planta primera F1.1 (Aula 14), Avenida de Roma s/n, 33011 Oviedo, Spain;1. INRA, UR1268 Biopolymers Interactions Assemblies F-44316 Nantes, France;2. Synchrotron SOLEIL, L''Orme des Merisiers, F-91190 Gif-sur-Yvette, France;3. UAR 1008 CEPIA, INRA, F-44316 Nantes, France;4. Sorbonne Universités, Université Pierre et Marie Curie, Paris VI, CNRS, Integrative Biology of Marine Models, UMR 8227, Station Biologique, Place George Teissier, F29688 Roscoff Cedex, France;1. Institut de Chimie des Substances Naturelles, UPR2301, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France;2. DISCO Beamline, Synchrotron SOLEIL, L’Orme des Merisiers, Saint-Aubin, 91192 Gif-sur-Yvette, France;3. UAR 1008 CEPIA, INRA, Rue de la Géraudière, F-44316 Nantes, France |
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| Abstract: | Transthyretin (TTR) is a ß-sheet-rich homotetrameric protein that transports thyroxine (T4) and retinol both in plasma and in cerebrospinal fluid. TTR also interacts with amyloid-β, playing a protective role in Alzheimer’s disease. Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloids fibrillogenesis, and is responsible for extracellular deposition of amyloid fibrils. Small molecules, able to bind in T4 binding sites and stabilize the TTR tetramer, are interesting tools to treat and prevent systemic ATTR amyloidosis. We report here the synthesis, in vitro evaluation and three-dimensional crystallographic analyses of new monoaryl-derivatives in complex with TTR. Of the derivatives reported here, the best inhibitor of TTR fibrillogenesis, 1d, exhibits an activity similar to diflunisal. |
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| Keywords: | Transthyretin Fibril formation inhibitors X-ray TTR-ligand complexes Monoaryl derivatives |
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