Resveratrol Derivatives Inhibit Transthyretin Fibrillization: Structural Insights into the Interactions between Resveratrol Derivatives and Transthyretin

Abstract

Hereditary ATTR amyloidosis is a disease caused by the deposition of amyloid fibrils formed by mutated transthyretin (TTR), a protein that binds to thyroid hormone in the serum, in the organs. The development of a small molecule that binds to and stabilizes TTR is a promising strategy for the treatment of ATTR amyloidosis. In the present study, we demonstrated that the resveratrol derivatives including pterostilbene available as a dietary supplement inhibit the fibrillization of V30M-TTR to the same extent as the approved drug tafamidis. Furthermore, based on a thermodynamic and X-ray crystallographic analysis, the binding of the resveratrol derivative to TTR was shown to be enthalpy-driven, with the binding enthalpy being acquired by hydrogen bonding to S117. Moreover, direct observation of hydrogen atoms by neutron crystallography provided details of the hydrogen bond network by S117 and emphasized the importance of the CH···π interaction by L110 in the ligand binding.

The Inhibition Effect of Epigallocatechin-3-Gallate on the Co-Aggregation of Amyloid-β and Human Islet Amyloid Polypeptide Revealed by Replica Exchange Molecular Dynamics Simulations

“…In comparison to chemical drugs, which may entail side-effects and higher costs, compounds derived from natural products offer advantages such as increased stability, safety and enhanced biological compatibility. Many natural polyphenol compounds (e.g., epigallocatechin-3-gallate (EGCG) [21,22], resveratrol [23,24] and curcumin [25,26]) have been found to have effective inhibition against amyloid protein aggregation. Among these polyphenol molecules, EGCG, as an extract from green tea, has the strongest inhibition effect [27,28].…”