Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation

Transthyretin amyloidosis
(ATTR) is a group of fatal diseases described
by the misfolding and amyloid deposition of transthyretin (TTR). Discovering
small molecules that bind and stabilize the TTR tetramer, preventing
its dissociation and subsequent aggregation, is a therapeutic strategy
for these pathologies. Departing from the crystal structure of TTR
in complex with tolcapone, a potent binder in clinical trials for
ATTR, we combined rational design and molecular dynamics (MD) simulations
to generate a series of novel halogenated kinetic stabilizers. Among
them, M-23 displays one of the highest affinities for
TTR described so far. The TTR/M-23 crystal structure
confirmed the formation of unprecedented protein–ligand contacts,
as predicted by MD simulations, leading to an enhanced tetramer stability
both in vitro and in whole serum. We demonstrate
that MD-assisted design of TTR ligands constitutes a new avenue for
discovering molecules that, like M-23, hold the potential
to become highly potent drugs to treat ATTR.