A Snapshot of the Most Recent Transthyretin Stabilizers

Abstract

In recent years, several strategies have been developed for the treatment of transthyretin-related amyloidosis, whose complex clinical manifestations involve cardiomyopathy and polyneuropathy. In view of this, transthyretin stabilizers represent a major cornerstone in treatment thanks to the introduction of tafamidis into therapy and the entry of acoramidis into clinical trials. However, the clinical treatment of transthyretin-related amyloidosis still presents several challenges, urging the development of new and improved therapeutics. Bearing this in mind, in this paper, the most promising among the recently published transthyretin stabilizers were reviewed. Their activity was described to provide some insights into their clinical potential, and crystallographic data were provided to explain their modes of action. Finally, structure-activity relationship studies were performed to give some guidance to future researchers aiming to synthesize new transthyretin stabilizers. Interestingly, some new details emerged with respect to the previously known general rules that guided the design of new compounds.

Keywords: SAR; TTR; activity; binding affinity; crystallographic studies; stabilizers; structure–activity relationship studies; synthetic compounds; transthyretin.

Figure 1

Graphical representation of the human TTR crystal structure. All the structural figures were drawn by author using the Protein Data Bank (PDB) id and PyMol program scripts [16,17]. (a) TTR tetramer, Cys10 in red. (b) TTR monomer. (c) Left TTR-T4 binding mode (pdb id: 2ROX), right scheme of halogen-binding pockets (HBPs).

Figure 2

Chemical structures of tafamidis, diflunisal, tolcapone, and acoramidis.

Figure 3

Schematic representation of the main therapeutic strategies for the treatment of ATTR. (* still under study or in clinical trials).

Figure 4

Chemical structures of compounds 1–5.

Figure 5

Binding modes of compounds 1–3 versus tolcapone (pdb id: 6SUH, 8C85, and 8C86). (a) Overview of TTR in complex with compound 3. (b) Superposition of 1–3 and tolcapone. (c) Comparison between compounds 1 and 2. (d) Detailed view of compound 3 superposed on tolcapone.

Figure 6

TTR in complex with compounds 4 (pdb id: 7QC5) and 5 (pdb id: 8PM9, 8PMA, and 8PMO). (a) Superposition between the complexes of tolcapone and 4 with wt-TTR. (b) Comparison of compound 5 in complex with wt-TTR, V30M-TTR, and V122I-TTR.

Figure 7

SARs of the tolcapone-derived molecules. Changes with respect to the structure of tolcapone have been highlighted in different colors based on their function and relationships.

Figure 8

Chemical structures of compounds 6–7.

Figure 9

Graphical representation of T₄BPs’ surface: wt-TTR in complex with compound 6 (pdb id: 7ERH) (a) and V30M-TTR in complex with compound 7 (pdb id: 7ERH) (b).

Figure 10

Chemical structures of compounds 8–15.

Figure 11

Crystal structures of compounds 8–10 in complex with V30M-TTR. (a) Superposition of 8 and 9, pdb id 8II2 and 8II1, respectively. (b) Comparison between compounds 8, 9, and 10 (pdb id 8II4).

Figure 12

Compounds 11 and 14 in complex with V30M-TTR. (a) Double binding mode of 11 in the T₄BP (pdb id 8WGS). (b) Pose of derivative 14 in the TTR cavity (pdb id 8WGT).

Figure 13

SAR for the reported scaffold, as described in [129].