Tafamidis is a kinetic stabilizer of transthyretin (TTR) that prevents amyloidogenesis by wild-type and mutant TTRs.
1 It binds to TTR with negative cooperativity (K
d1 = 3 nM; K
d2 = 278 nM) to stabilize the TTR dimer-dimer interface and inhibit tetrameric dissociation. Tafamidis stabilizes wild-type and clinically significant V30M and V122I mutant TTR amyloidogenic homotetramers (EC
50s = 2.7-3.2 μM) under fibril-promoting, denaturing, and physiological conditions
in vitro. It stabilizes TTR heterotetramers containing wild-type and mutant subunits
ex vivo in human plasma derived from patients carrying V30M or V1221 mutations when used at a concentration of 7.2 μM. Formulations containing tafamidis have been used for the treatment of familial amyloid polyneuropathy.
2