Skip to Main content Skip to Navigation
Journal articles

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

Abstract : Transthyretin (TTR) is a beta-sheet-rich homotetrameric protein that transports thyroxine (T4) and retinol both in plasma and in cerebrospinal fluid. TTR also interacts with amyloid-beta, 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.
Complete list of metadata

https://hal.inrae.fr/hal-03320759
Contributor : Camille Serva <>
Submitted on : Monday, August 16, 2021 - 1:34:26 PM
Last modification on : Monday, August 30, 2021 - 8:58:42 AM

Identifiers

Citation

Lidia Ciccone, Susanna Nencetti, Nicolo Tonali, Carole Fruchart-Gaillard, William Shepard, et al.. Monoaryl derivatives as transthyretin fibril formation inhibitors: Design, synthesis, biological evaluation and structural analysis. Bioorganic & Medicinal Chemistry Letters, 2020, 28 (18), ⟨10.1016/j.bmc.2020.115673⟩. ⟨hal-03320759⟩

Share

Metrics

Record views

18