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.
摘要：
野生型转甲状腺素蛋白（TTR）和超过130种遗传TTR变体的聚集是一组致命疾病的基础，称为TTR淀粉样变性（ATTR）。TTR化学伴侣是对改变ATTR进展过程具有巨大前景的分子。在以往的研究中,我们结合了合理的设计和分子动力学模拟，以产生一系列TTR选择性动力学稳定剂，显示出极高的亲和力。为了支持先前开发的具有最佳药代动力学特性的分子，我们进行了结构设计优化，导致PITB的发展。PITB以高亲和力结合TTR，有效抑制野生型蛋白和两种最普遍的疾病相关TTR变体的四聚体解离和聚集。重要的是,PITB选择性结合并稳定血浆中的TTR，胜过托卡彭,目前正在接受ATTR临床试验的药物。对小鼠进行的药代动力学研究证实，PITB表现出令人鼓舞的药代动力学特性，正如最初的意图。此外，PITB显示出优异的口服生物利用度和缺乏毒性。这些组合属性将PITB定位为未来临床试验的先导化合物，作为ATTR的疾病改善疗法。
