8PM8

V30M Transthyretin structure in complex with Tolcalpone

8PM8 の概要

• エントリーDOI: 10.2210/pdb8pm8/pdb
• 分子名称: Transthyretin, Tolcapone (3 entities in total)
• 機能のキーワード: aggregation, inhibitor, amyloid, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28165.33

構造登録者

Varejao, N.,Pinheiro, F.,Pallares, I.,Ventura, S.,Reverter, D. (登録日: 2023-06-28, 公開日: 2024-05-08)

主引用文献

Pinheiro, F.,Varejao, N.,Sanchez-Morales, A.,Bezerra, F.,Navarro, S.,Velazquez-Campoy, A.,Busque, F.,Almeida, M.R.,Alibes, R.,Reverter, D.,Pallares, I.,Ventura, S.
PITB: A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties.
Eur.J.Med.Chem., 261:115837-115837, 2023

PubMed Abstract: 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.

PubMed: 37837673
DOI: 10.1016/j.ejmech.2023.115837

実験手法

X-RAY DIFFRACTION (1.57 Å)