Design of Small Molecules to Modulate Transthyretin Aggregation

Abstract

Transthyretin (TTR) amyloid deposits have been causally implicated in familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC). An effective means to block formation and disaggregate transthyretin amyloid deposits of patients with FAP and FAC does not exist. We have designed and synthesized small molecules to stop formation of, as well as disaggregate these deposits. Our hypothesis is that TTR fibrils can be abrogated by TTR‐interactive compounds. The specific aim of this study is to define the activity of our novel small molecules on TTR aggregation and disaggregation with biophysical methods. Thioflavin T (ThT) fluorescence assay was used to monitor fibril formation with synthetic TTR truncated peptide (TTR81–127) treated with small molecules. At the end of a time‐course study, fibrils were directly detected by transmission electron microscopy. Preliminary results showed a few molecules that were able to abrogate fibril formation via the ThT fluorescence assay. The percentages of fibril formation measured at the plateau phase of the kinetics of fibril formation obtained with control and the most potent molecules were compared. One of our best compounds, JF‐19‐029, was ten time more potent than the positive control, resveratrol in inhibiting fibril formation. When TTR81–127 was incubated for 24h with JF‐19‐029, rarely fibrils were observed on the copper grid visualized with the electron microscope. This compound is also being studied to determine the potential for disaggregation of mature TTR81–127 fibrils. This project discovered novel small molecules that potentially reduce TTR fibril formation, with the eventual goal to improve the therapeutic arsenal for FAP and FAC.