Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis

Transthyretin (TTR) amyloid cardiomyopathy
(ATTR-CM) is a fatal
disease with no available disease-modifying therapies. While pathogenic
TTR mutations (TTRm) destabilize TTR tetramers, the T119M variant
stabilizes TTRm and prevents disease. A comparison of potency for
leading TTR stabilizers in clinic and structural features important
for effective TTR stabilization is lacking. Here, we found that molecular
interactions reflected in better binding enthalpy may be critical
for development of TTR stabilizers with improved potency and selectivity.
Our studies provide mechanistic insights into the unique binding mode
of the TTR stabilizer, AG10, which could be attributed to mimicking
the stabilizing T119M variant. Because of the lack of animal models
for ATTR-CM, we developed an in vivo system in dogs which proved appropriate
for assessing the pharmacokinetics–pharmacodynamics profile
of TTR stabilizers. In addition to stabilizing TTR, we hypothesize
that optimizing the binding enthalpy could have implications for designing
therapeutic agents for other amyloid diseases.