Amyloidogenic proteins share a common structural feature of beta-sheet rich aggregates that bind Congo red and exhibit apple-green birefringence under polarized light. In transthyretin (TTR) amyloidosis (ATTR), the native tetrameric TTR dissociates to monomers that misfold and aggregate. Tafamidis is a small molecule that treats ATTR cardiomyopathy. What is its mechanism of action?

• A Tafamidis inhibits fibril elongation by capping growing amyloid fibrils
• B Tafamidis activates the ubiquitin-proteasome system to degrade misfolded TTR monomers
• C Tafamidis binds the thyroxine-binding sites of TTR tetramer, kinetically stabilizing the tetramer and preventing dissociation to amyloidogenic monomers ✓
• D Tafamidis is an antisense oligonucleotide that reduces TTR mRNA translation in hepatocytes

Explanation

Tafamidis (Vyndaqel) binds selectively and with high affinity to the thyroxine (T4)-binding sites of the TTR tetramer (TTR has two T4 binding sites at the dimer-dimer interface). By occupying these sites, tafamidis kinetically stabilizes the native tetrameric quaternary structure of TTR, preventing the rate-limiting tetramer dissociation step that leads to amyloidogenic monomer formation and aggregation. This stabilization approach is distinct from small interfering RNA (patisiran) or antisense oligonucleotides (inotersen) which reduce hepatic TTR production. Diflunisal is an older TTR stabilizer. The ATTR-ACT trial established tafamidis's clinical benefit in ATTR cardiomyopathy. Understanding tetramer stabilization as the mechanism is central to NEET PG pharmacology and molecular basis of amyloidosis.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.