Transthyretin Amyloidogenesis Inhibitors: From Discovery to Current Developments

Area of Science:

• Biochemistry
• Protein Misfolding Diseases
• Drug Discovery

Background:

• Transthyretin (TTR) is a plasma protein that forms amyloid fibrils upon dissociation and misfolding.
• Hereditary transthyretin amyloidosis involves extracellular deposition of TTR amyloid fibrils.
• Current treatments include TTR synthesis inhibitors and TTR tetramer stabilizers.

Purpose of the Study:

• To describe representative kinetic stabilizers of the TTR tetramer.
• To detail the discovery and development process of these stabilizers.
• To integrate crystallographic studies of TTR-stabilizer complex structures.

Main Methods:

• Literature review of TTR stabilizers.
• Analysis of crystallographic data for TTR-stabilizer complexes.
• Discussion of drug discovery and development pathways.

Main Results:

• Several small molecules have been identified as kinetic stabilizers of the TTR tetramer.
• Tafamidis is an approved TTR stabilizer.
• Nucleic acid medicines (inotersen, patisiran) inhibit TTR synthesis.

Conclusions:

• Kinetic stabilization of the TTR tetramer is a viable therapeutic strategy for hereditary TTR amyloidosis.
• Crystallographic studies are crucial for understanding stabilizer mechanisms.
• Continued development of TTR stabilizers holds promise for treating this disorder.