Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its Aggregation

Transthyretin
(TTR) is a homotetrameric protein. Its dissociation
into monomers leads to the formation of fibrils that underlie human
amyloidogenic diseases. The binding of small molecules to the thyroxin-binding
sites in TTR stabilizes the homotetramer and attenuates TTR amyloidosis.
Herein, we report on boronic acid-substituted stilbenes that limit
TTR amyloidosis in vitro. Assays of affinity for TTR and inhibition
of its tendency to form fibrils were coupled with X-ray crystallographic
analysis of nine TTR·ligand complexes. The ensuing structure–function
data led to a symmetrical diboronic acid that forms a boronic ester
reversibly with serine 117. This diboronic acid inhibits fibril formation
by both wild-type TTR and a common disease-related variant, V30M TTR,
as effectively as does tafamidis, a small-molecule drug used to treat
TTR-related amyloidosis in the clinic. These findings establish a
new modality for covalent inhibition of fibril formation and illuminate
a path for future optimization.