Small molecule stabilizer of transthyretin tetramer

Abstract

Transthyretin (TTR) amyloidosis is a disease that causes amyloid deposits in the heart, kidneys, gastrointestinal tract, and eyes. Small molecule drug discovery is being carried out with a strategy of stabilizing the TTR structure and inhibiting amyloid fibril formation. Tafamidis, AG10, diflunisal and tolcapone are known as small molecule drugs. The potency and efficacy of these small molecule stabilizers were found to correlate with the binding enthalpy with TTR. X-ray crystallography revealed that AG10-TTR mutant complex recreated the structure of the T119M-TTR mutant. NMR analysis showed that the difference in main chain chemical shift between wild-type TTR and mutant TTR resulted in significant structural differences between them.