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

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.

Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant

“…More than 130 mutational variants of transthyretin have been documented, with many showing associations for specific disease symptoms 4 . The influence of each mutational variant on the clinical phenotype is not yet fully understood, and some studies suggest that could be related to their effects on fibril formation, structure, or both 5,6 .…”

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

“…This depends, of course, on the length of the amyloidogenic run of amino acids that forms it, but is typically 1-2nm or so. A protofibril consisting of 2-4 intertwined monomer fibrils may be 4-11nm for molecules such as Aβ [212], 7nm for tau [213], 11nm for the prion protein in its amyloid PrP Sc form [214], 6-15 nm for α-synuclein [215,216], and 7-13 nm for transthyretin [217].…”

The Journey of Human Transthyretin: Synthesis, Structure Stability, and Catabolism

“…Human TTR is a homotetrameric, slightly acidic (isoelectric point of 5.3) protein with a molecular mass of 55 kDa composed of four identical monomers, with a molecular weight of approximately 14 kDa [ 62 ]. Each monomer consists of eight β-strands structures designated with letters from “A” to “H” and one short α-helix of nine residues included between strands E and F. All strand interactions are antiparallel except for the interaction between strands A and G. These eight β-strands are connected by loops and are arranged in two groups of twisted β-sheets [ 44 , 63 , 64 ]. Interstrand hydrogen bonds allow the organisation of a tertiary structure of β-strands constituted by an inner (strands DAGH) and an outer (strands CBEF) β-sheet, which are orthogonal to one another [ 44 , 63 , 64 ] ( Figure 1 ).…”

“…Two TTR monomers are arranged into dimers by hydrogen bonding between two F (F, F’) and two H (H, H’) strands from adjacent monomers. This provides an extensive contact region where the β-sheets are strictly packed in a layer-by-layer manner contributing to the stability of the molecules [ 44 , 63 , 64 ].…”

“…Indeed, the dimer is thought to be the basic structural unit of mature TTR. This perspective is strengthened by the observation that the contact region between dimers is smaller than those between monomers and consists of hydrophobic and hydrophilic interactions [ 44 , 63 , 64 ]. Thus, in physiological conditions, TTR is a globular homo-tetramer organised as a dimer of dimers.…”