Review on the Structures and Activities of Transthyretin Amyloidogenesis Inhibitors

Abstract

Transthyretin (TTR) is a tetrameric protein, and its dissociation, aggregation, deposition, and misfolding are linked to several human amyloid diseases. As the main transporter for thyroxine (T4) in plasma and cerebrospinal fluid, TTR contains two T4-binding sites, which are docked with T4 and subsequently maintain the structural stability of TTR homotetramer. Affected by genetic disorders and detrimental environmental factors, TTR degrades to monomer and/or form amyloid fibrils. Reasonably, stabilization of TTR might be an efficient strategy for the treatment of TTR-related amyloidosis. However, only 10–25% of T4 in the plasma is bound to TTR under physiological conditions. Expectedly, T4 analogs with different structures aiming to bind to T4 pockets may displace the functions of T4. So far, a number of compounds including both natural and synthetic origin have been reported. In this paper, we summarized the potent inhibitors, including bisaryl structure-based compounds, flavonoids, crown ethers, and carboranes, for treating TTR-related amyloid diseases and the combination modes of some compounds binding to TTR protein.

Keywords:

• transthyretin
• amyloidogenesis
• stabilization
• inhibitors

Acknowledgments

This study was financially supported by the National Natural Science Foundation of China (81660371, 81860388, 81860261, and 81960883), The Youth Jinggang Scholar Program in Jiangxi Province, and Innovative Teamwork Project of Gannan Medical University (TD201707).

Data Sharing Statement

The experimental data used to support the findings of this study are included within the article.

Author Contributions

All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest in this work.