Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors: Synthesis, Evaluation, and Mechanism of Action

Abstract

Benzoxazoles pevent misfolding: Benzoxazole-based inhibitors of transthyretin (TTR) amyloid fibril formation are among the most effective found to date. They stabilize TTR against both acid-mediated misfolding and urea denaturation by raising the activation barrier to tetramer dissociation, the rate-limiting step for amyloid formation. The figure depicts the cocrystal structure of one of the better benzoxazole inhibitors bound to TTR.