| Autor: |
Francisca Pinheiro, Irantzu Pallarès, Francesca Peccati, Adrià Sánchez-Morales, Nathalia Varejão, Filipa Bezerra, David Ortega-Alarcon, Danilo Gonzalez, Marcelo Osorio, Susanna Navarro, Adrián Velázquez-Campoy, Maria Rosário Almeida, David Reverter, Félix Busqué, Ramon Alibés, Mariona Sodupe, Salvador Ventura |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Popis: |
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. 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
