转甲状腺素
化学
药代动力学
小分子
四聚体
药理学
计算生物学
药物发现
药品
生物利用度
生物化学
医学
酶
内科学
生物
作者
Francisca Pinheiro,Nathalia Varejāo,Adrià Sánchez-Morales,Filipa Bezerra,Susanna Navarro,Adrián Velázquez‐Campoy,Félíx Busqué,Maria Rosário Almeida,Ramón Alibés,David Reverter,Irantzu Pallarès,Salvador Ventura
标识
DOI:10.1016/j.ejmech.2023.115837
摘要
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 PTIB. 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 PTIB exhibits encouraging pharmacokinetic properties, as originally intended. Furthermore, PTIB 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.
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