DESIGN OF BIFUNCTIONAL SMALL MOLECULES MODULATING PROTEIN-PROTEIN INTERACTIONS IN PRION DISEASES

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are neurodegenerative and infectious disorders that affect both humans and animals, and are not curable with drugs. TSEs are typical conformational diseases, where the cellular form of the prion protein (PrPC) is converted to a misfolded variant (PrPSc) through a nucleated polymerization involving protein-protein interactions (PPIs). The conformational transition of the prion protein results in a decrease in part of the -helical folding and a concomitant increase in the -sheet content of PrPSc. As seen in other amyloidoses, the PrPSc isoform is prone to forming aggregates and displays a pronounced resistance to proteases. The aggregates, which accumulate in association with neurons in affected brain areas, are thought to be responsible of the spongiform degeneration and neuronal death observed in infected hosts. From a medicinal chemistry perspective, all conformational diseases are ‘black boxes’ because the three-dimensional structure and the mechanistic properties of the target are not available. Although reliable proof-of-principle was demonstrated in a variety of experimental models, and several small molecules have been identified as active against TSE [Trevitt, 2006], the molecular mechanism of action for most of these molecules remains largely unexplored. Thus, it emerges that the rational design of antiprion compounds is still a big challenge. However, a favourable point that could further motivate drug discovery in prion diseases is that the lessons we can learn from their investigation with small molecules might have an impact on other neurodegenerative conformational diseases, such as Alzheimer’s disease. In an effort to identify antiprion lead compounds with unprecedented molecular frameworks, we envisaged the planar 2,5-bis-diamino-benzoquinone and 3,6-dimethylenepiperazine-2,5-dione scaffolds as privileged motifs in modulating PPIs in prions. Building on these two fragments as appropriate spacers, we designed two series of a symmetrical bifunctional ligands that effectively inhibited prion replication in ScGT1 cells [Tran, 2010; Bolognesi, 2010]. Moreover, fibrillation studies suggested that they might interact directly with recombinant PrP to prevent its conversion to the pathogenic misfolded PrPSc form. These results validate our design rationale as a viable strategy for the identification of novel lead compounds with antiprion properties.