2. Academic Validation
  3. Monoaryl derivatives as transthyretin fibril formation inhibitors: Design, synthesis, biological evaluation and structural analysis

Monoaryl derivatives as transthyretin fibril formation inhibitors: Design, synthesis, biological evaluation and structural analysis

  • Bioorg Med Chem. 2020 Sep 15;28(18):115673. doi: 10.1016/j.bmc.2020.115673.
Lidia Ciccone 1,  Susanna Nencetti 2,  Nicolo Tonali 3,  Carole Fruchart-Gaillard 4,  William Shepard 5,  Elisa Nuti 6,  Caterina Camodeca 6,  Armando Rossello 7,  Elisabetta Orlandini 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy; Synchrotron SOLEIL, L'Orme des Merisiers, Saint-Aubin, BP 48, 91192 Gif-sur-Yvette, France.
  • 2 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy. Electronic address: [email protected].
  • 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 Synchrotron SOLEIL, L'Orme des Merisiers, Saint-Aubin, BP 48, 91192 Gif-sur-Yvette, France.
  • 6 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
  • 7 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy; Research Center "E. Piaggio", Università di Pisa, Pisa 56122, Italy.
  • 8 Department of Earth Sciences, University of Pisa, Via Santa Maria 53-55, 56100 Pisa, Italy; Research Center "E. Piaggio", Università di Pisa, Pisa 56122, Italy. Electronic address: [email protected].
PMID: 32828431 DOI: 10.1016/j.bmc.2020.115673
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.

Keywords

Fibril formation inhibitors; Monoaryl derivatives; Transthyretin; X-ray TTR-ligand complexes.

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