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

Pinheiro, Francisca ; Varejão, Nathalia ; Sánchez-Morales, Adrià ; Bezerra, Filipa ; Navarro, Susanna ; Velázquez-Campoy, Adrián (Universidad de Zaragoza) ; Busqué, Félix ; Almeida, Maria Rosário ; Alibés, Ramon ; Reverter, David ; Pallarès, Irantzu ; Ventura, Salvador

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: Inglés

DOI: 10.1016/j.ejmech.2023.115837

Año: 2023

Publicado en: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 261 (2023), 115837 [10 pp.]
ISSN: 0223-5234

Factor impacto JCR: 6.0 (2023)

Categ. JCR: CHEMISTRY, MEDICINAL rank: 8 / 72 = 0.111 (2023) - Q1 - T1

Factor impacto CITESCORE: 11.7 - Pharmacology (Q1) - Organic Chemistry (Q1) - Drug Discovery (Q1)

Factor impacto SCIMAGO: 1.151 - Drug Discovery (Q1) - Pharmacology (Q1) - Organic Chemistry (Q1) - Medicine (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PDC2021-120914-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2021-124602OB-I00
Financiación: info:eu-repo/grantAgreement/ES/MINECO/PID2019-106403RB-I00

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)