PITB : A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties

Francisca Pinheiro, Nathalia Varejão, Adrià Sánchez-Morales, Filipa Bezerra, Susanna Navarro, Adrian Velázquez-Campoy, Félix Busqué Sánchez, Maria Rosário Almeida, Ramón Alibes, David Reverter, Irantzu Pallarès i Goitiz, Salvador Ventura

Producción científica: Contribución a una revistaArtículoInvestigaciónrevisión exhaustiva

Resumen

The aggregation of wild-type transthyretin (TTR) and over 130 genetic TTR variants underlies a group of lethal disorders named TTR amyloidosis (ATTR). TTR chemical chaperones are molecules that hold great promise to modify the course of ATTR progression. In previous studies, we combined rational design and molecular dynamics simulations to generate a series of TTR selective kinetic stabilizers displaying exceptionally high affinities. In an effort to endorse the previously developed molecules with optimal pharmacokinetic properties, we conducted structural design optimization, leading to the development of PITB. PITB binds with high affinity to TTR, effectively inhibiting tetramer dissociation and aggregation of both the wild-type protein and the two most prevalent disease-associated TTR variants. Importantly, PITB selectively binds and stabilizes TTR in plasma, outperforming tolcapone, a drug currently undergoing clinical trials for ATTR. Pharmacokinetic studies conducted on mice confirmed that PITB exhibits encouraging pharmacokinetic properties, as originally intended. Furthermore, PITB demonstrates excellent oral bioavailability and lack of toxicity. These combined attributes position PITB as a lead compound for future clinical trials as a disease-modifying therapy for ATTR.
Idioma originalInglés
Número de artículo115837
Número de páginas10
PublicaciónCHIM.THER.
Volumen261
DOI
EstadoPublicada - 5 dic 2023

Huella

Profundice en los temas de investigación de 'PITB : A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties'. En conjunto forman una huella única.

Citar esto