<p>Review on the Structures and Activities of Transthyretin Amyloidogenesis Inhibitors</p>

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 T4binding 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 structurebased compounds, flavonoids, crown ethers, and carboranes, for treating TTR-related amyloid diseases and the combination modes of some compounds binding to TTR protein.

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

“…Currently, more than 400 crystallographic structures of TTR are deposited in the Protein Data Bank ( ) [ 17 ], most of them in complex with small-molecule ligands. This comprehensive work has allowed a full characterization of the TTR binding sites [ 18 , 19 , 20 ]. A relevant feature of these sites is the presence of three sets of symmetry-related depressions termed halogen-binding pockets (HBPs: HBP1 and HBP1’, HBP2 and HBP2’ and HBP3 and HBP3’), which accommodate the iodine atoms of the thyroid hormones in their complexes with TTR [ 21 ].…”

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

“…Familial amyloid polyneuropathy (FAP) is another TTR amyloidosis and is usually associate to Val30Met point mutation [106]. One therapeutic strategy against TTR amyloidosis is the tetramer stabilization by small molecules such as bisaryl [109,110] or monoaryl [111][112][113] structure-based compounds or natural molecules [114,115].…”

Molecular Mechanisms of Inhibition of Protein Amyloid Fibril Formation: Evidence and Perspectives Based on Kinetic Models

“…Therefore, in the present paper, we review the previous studies of various inhibitors acting on different proteins in light of the molecular mechanism of action and kinetics of aggregation. A number of other reviews have also been published focusing on the various aspects of fibril formation inhibition, namely on the diversity of the chemical structure of inhibitors [ 3 , 21 , 22 ], on polymer materials showing inhibitory activity [ 17 , 23 ], on peptide-based inhibitors [ 24 ], or particularly on human beta-amyloid inhibitors and treatment strategies of Alzheimer’s disease [ 25 , 26 , 27 ] and transthyretin amyloidogenesis inhibitors [ 28 ].…”