Review on the Structures and Activities of Transthyretin Amyloidogenesis Inhibitors

Review on the Structures and Activities of Transthyretin Amyloidogenesis Inhibitors

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Xiaohua Guo,* Zhaowen Liu,* Yizhou Zheng, Yamei Li, Linfu Li, Hai Liu, Zhixi Chen, Longhuo Wu College of Pharmacy, Gannan Medical University, Ganzhou 341000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Longhuo Wu Email longhwu@hotmail.comAbstract: Transthyretin (TTR) is a tetrameric protein, and its dissociation, red pygmy dogwood 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 mpu63zm/a 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.