Reduction of the amyloidogenicity of a protein by specific binding of ligands to the native conformation

It is known that human muscle acylphosphatase (AcP) is able, under appropri ate conditions in vitro, to aggregate and form amyloid fibrils of the type associated with human diseases. A number of compounds were tested for their ability to bind specifically to the native conformation of AcP under condi tions favoring denaturation and subsequent aggregation and fibril formation . Compounds displaying different binding affinities for AcP were selected a nd their ability to inhibit protein fibrillization in vitro was evaluated. We found that compounds displaying a relatively high affinity for AcP are a ble to significantly delay protein fibrillization, mimicking the effect of stabilizing mutations; in addition, the effectiveness of such outcome corre lates positively to both ligand concentration and affinity to the native st ate of AcP. By contrast, the inhibitory effect of ligands on AcP aggregatio n disappears in a mutant protein in which such binding affinity is lost. Th ese results indicate that the stabilization of the native conformation of a myloidogenic proteins by specific ligand binding can be a strategy of gener al interest to inhibit amyloid formation in vivo.