Blinded potency comparison of transthyretin kinetic stabilisers by subunit exchange in human plasma.

ABSTRACT: Transthyretin (TTR) tetramer dissociation is rate limiting for aggregation and subunit exchange. Slowing of TTR tetramer dissociation via kinetic stabiliser binding slows cardiomyopathy progression. Quadruplicate subunit exchange comparisons of the drug candidate AG10, and the drugs tolcapone, diflunisal, and tafamidis were carried out at 1, 5, 10, 20 and 30 µM concentrations in 4 distinct pooled wild type TTR (TTRwt) human plasma samples. These experiments reveal that the concentration dependence of the efficacy of each compound at inhibiting TTR dissociation was primarily determined by the ratio between the stabiliser's dissociation constants from TTR and albumin, which competes with TTR to bind kinetic stabilisers. The best stabilisers, tafamidis (80 mg QD), AG10 (800 mg BID), an

SUBMITTER: Nelson LT 

PROVIDER: S-EPMC7952025 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature