Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation

• Published in: Journal of medicinal chemistry Vol. 65; no. 21; pp. 14673 - 14691
• Main Authors: Pinheiro, Francisca, Pallarès, Irantzu, Peccati, Francesca, Sánchez-Morales, Adrià, Varejão, Nathalia, Bezerra, Filipa, Ortega-Alarcon, David, Gonzalez, Danilo, Osorio, Marcelo, Navarro, Susanna, Velázquez-Campoy, Adrián, Almeida, Maria Rosário, Reverter, David, Busqué, Félix, Alibés, Ramon, Sodupe, Mariona, Ventura, Salvador
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.11.2022; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; DIFLUNISAL; PROTEIN; HELA-CELLS; FAMILIAL AMYLOIDOTIC POLYNEUROPATHY; SEQUENCE; MOLECULAR-DYNAMICS SIMULATIONS; TOLCAPONE; VARIANT; BINDING; QUATERNARY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01195

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.