Home > Articles > Published articles > Development of a highly potent transthyretin amyloidogenesis inhibitor : |
Date: | 2022 |
Abstract: | Transthyretin amyloidosis (ATTR) is a group of fatal diseases described by the misfolding and amyloid deposition of transthyretin (TTR). Discovering small molecules that bind and stabilize the TTR tetramer, preventing its dissociation and subsequent aggregation, is a therapeutic strategy for these pathologies. Departing from the crystal structure of TTR in complex with tolcapone, a potent binder in clinical trials for ATTR, we combined rational design and molecular dynamics (MD) simulations to generate a series of novel halogenated kinetic stabilizers. Among them, M-23 displays one of the highest affinities for TTR described so far. The TTR/ M-23 crystal structure confirmed the formation of unprecedented protein-ligand contacts, as predicted by MD simulations, leading to an enhanced tetramer stability both in vitro and in whole serum. We demonstrate that MD-assisted design of TTR ligands constitutes a new avenue for discovering molecules that, like M-23, hold the potential to become highly potent drugs to treat ATTR. |
Grants: | Agencia Estatal de Investigación PDC2021-120914-I00 Agencia Estatal de Investigación PID2019-105017RB-I00 Ministerio de Economía y Competitividad PID2019-106403RB-IOO Ministerio de Economía y Competitividad BIO2016-78310-R Ministerio de Economía y Competitividad BFU2016-78232-P Ministerio de Economía y Competitividad CTQ2016-75363-R |
Note: | Altres ajuts: this work was funded by ICREA, ICREA-Academia 2015 and 2020 to S.V. F.P. and A.S. acknowledge the Universitat Autònoma de Barcelona for their doctoral grant. This work was funded by FEDER through COMPETE 2020 and N2020 through PT2020 and HEALTH-UNORTE: NORTE-01-0145-FEDER-000039 to M.R.A. |
Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Subject: | Cavities ; Kinetics ; Ligands ; Molecules ; Plasma |
Published in: | Journal of Medicinal Chemistry, Vol. 65, issue 21 (Nov. 2022) , p. 14673-14691, ISSN 1520-4804 |
19 p, 6.1 MB |