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.
Original languageEnglish
Article number115837
Number of pages10
JournalCHIM.THER.
Volume261
DOIs
Publication statusPublished - 5 Dec 2023

Keywords

  • Amyloidosis
  • Lead optimization
  • Pharmacokinetics
  • Stabilizers
  • Transthyretin
  • V30M

Fingerprint

Dive into the research topics of 'PITB : A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties'. Together they form a unique fingerprint.

Cite this