Transthyretin Amyloidogenesis Inhibitors: From Discovery to Current Developments.

Takeshi Yokoyama, Mineyuki Mizuguchi

Journal of medicinal chemistry 2020 Dec 10

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Transthyretin (TTR) is a homotetrameric protein in human plas ma. The dissociation of the TTR tetramer and misfolding of the TTR monomer result in the formation of amyloid fibrils. Hereditary TTR amyloidosis is characterized by the extracellular deposition of amyloid fibrils containing TTR variants. The development of small molecules that kinetically stabilize the TTR tetramer is one of the effective strategies for the treatment of hereditary TTR amyloidosis. So far, several stabilizers have been discovered. Tafamidis is the only approved stabilizer for treatment of hereditary TTR amyloidosis, although two nucleic acid medicines that inhibit TTR synthesis, inotersen and patisiran, were recently approved for treatment of this disorder. In this Perspective, we seek to describe the representative kinetic stabilizers from discovery to development, interweaving the crystallographic study of the complex structures.

Citation

Takeshi Yokoyama, Mineyuki Mizuguchi. Transthyretin Amyloidogenesis Inhibitors: From Discovery to Current Developments. Journal of medicinal chemistry. 2020 Dec 10;63(23):14228-14242