Raising barriers to provide protection is a familiar form of defence, so it should be no surprise to find out that nature has also adopted this method to protect against diseases. In protein folding diseases, energy barriers control the misfolding of proteins — low barriers allow the protein to misfold rapidly, whereas high barriers prevent this. In one group of protein misfolding diseases — the transthryretin (TTR) amyloid diseases — mutations on one allele can cause TTR protein tetramers to dissociate and misfold, and then misassemble into insoluble amyloid fibrils. However, mutations on the other allele can raise the kinetic barrier of this process, stabilizing the native state and making it harder for the normal TTR tetramer to dissociate and misfold.

Jeffrey Kelly and colleagues report in Science how they have taken advantage of this defence mechanism, called trans-suppression, to develop small-molecule inhibitors that can carry out the same task. The first step was to understand the mechanism of trans-suppression. Looking at engineered tetramers that contained disease-causing subunits and trans-suppressing subunits, the authors found that trans-suppression is principally mediated through increasing the activation energy associated with the dissociation of the tetramer (the rate-limiting step of TTR amyloid-fibril production) to such a degree that the barrier becomes insurmountable.

Known small-molecule inhibitors of amyloidogenesis are also thought to function by shifting the equilibrium away from the amyloid-fibril state, not by stopping the process of aggregation. Kelly and colleagues looked at five small-molecule inhibitors of TTR amyloidogenesis — including diflunisal and diclofenac, two FDA-approved non-steroidal anti-inflammatory drugs (NSAIDs) — and found that these function similarly to the trans-suppressor and stabilize the native protein state in a dose-dependent manner by increasing the activation energy for tetramer dissociation.

This is the first time that small-molecule inhibitors have been shown to stop protein-folding diseases before they begin. Most therapeutic strategies to date have focused on targeting the later stages of the aggregation process, but there is growing evidence that early misfolded intermediates are the toxic form of the misfolded protein, and that therefore the damage might might not be influenced significantly by inhibitors that prevent the later stages of amyloid-fibril formation. The hope is that raising the energy barriers of protein misfolding using small-molecule inhibitors could be extended to other protein folding diseases, such as Alzheimer's disease and Parkinson's disease.