Crown Ethers as Transthyretin Amyloidogenesis Inhibitors

Transthyretin
(TTR) is a tetrameric protein found in human serum
and associated with amyloid diseases. Because the tetramer dissociation
and misfolding of the monomer precede amyloid fibril formation, development
of a small molecule that binds to TTR and stabilizes the TTR tetramer
is an efficient strategy for the treatment of amyloidosis. Here, we
report our discovery of the anti-TTR amyloidogenesis activities of
crown ethers. X-ray crystallographic analysis, binding assay, and
chemical cross-linking assay showed that 4′-carboxybenzo-18C6
(4) stabilized the TTR tetramer by binding to the allosteric
sites on the molecular surface of the TTR tetramer. In addition, 4 synergistically increased the stabilization activity of
diflunisal, one of the most potent TTR amyloidogenesis inhibitors.
These experimental evidences establish that 4 is a valuable
template compound as an allosteric inhibitor of TTR amyloidogenesis.