The Structural Understanding of Transthyretin Misfolding and the Inspired Drug Approaches for the Treatment of Heart Failure Associated With Transthyretin Amyloidosis.

Shan He,Zhang Feiyi,Shuyang Zhang,Yue Fan,Zhun Deng,Lanlan Yu,Xinyue He,Xinyue Zhao,Lun Wang,Wenbo Zhang,Lei Liu,Chenxuan Wang,Shanshan Mo

doi:10.3389/fphar.2021.628184

Abstract

Substantial controversies exist in the exploration of the molecular mechanism of heart failure (HF) and pose challenges to the diagnosis of HF and the discovery of specific drugs for the treatment. Recently, cardiac transthyretin (TTR) amyloidosis is becoming recognized as one of major causes of underdiagnosed HF. The investigation and modulation of TTR misfolding and amyloidal aggregation open up a new revenue to reveal the molecular mechanisms of HF and provide new possibilities for the treatment of HF. The aim of this review is to briefly introduce the recent advances in the study of TTR native and misfolding structures, discuss the correlation between the genotype and phenotype of cardiac TTR amyloidosis, and summarize the therapeutic applications of TTR structural stabilizers in the treatment of TTR amyloidosis-associated HF.

Highlights

Heart failure (HF) is a clinical syndrome that originates from the insufficient cardiac output to accommodate the need of peripheral tissues or organs due to the cardiac systolic or diastolic dysfunction (McMurray and Pfeffer, 2005)
We summarize the recent structural and medical advances of cardiac TTR amyloidosis studies
The plausible mechanism underlying the stabilizing impact by thyroxine mimic is attributed to the elevated energy barrier of TTR tetramer dissociation leading to less amyloidal fibril formation and reducing the rate of amyloidogenesis progression (Johnson et al, 2012)

Summary

INTRODUCTION

Heart failure (HF) is a clinical syndrome that originates from the insufficient cardiac output to accommodate the need of peripheral tissues or organs due to the cardiac systolic or diastolic dysfunction (McMurray and Pfeffer, 2005). The cardiac phenotype-related pathogenic site accelerates the rate-limiting step of dissociation of tetramers into monomers, resulting in massive formation of TTR amyloidal aggregates and the accumulation of the clinical phenotype of HF. The plausible mechanism underlying the stabilizing impact by thyroxine mimic is attributed to the elevated energy barrier of TTR tetramer dissociation leading to less amyloidal fibril formation and reducing the rate of amyloidogenesis progression (Johnson et al, 2012). The general molecular mechanism of structural stabilizer can be applied to interpret the pharmacological activity that tafamidis selectively occupies the thyroxine binding site, preventing the structural conversion from native tetramer to denatured monomers (Figure 1B).

Design of

Findings

CONCLUSION