RATIONAL DISCOVERY OF MULTI-TARGET AGENTS FOR PRION DISEASES

Prion diseases are prototypical conformational diseases. From a medicinal chemistry point of view, all conformational diseases are ‘black boxes’ because the three-dimensional structure and the mechanistic properties of the target are not fully 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. In an effort to rationally discover antiprion lead compounds, 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 symmetrical bifunctional ligands that effectively inhibited prion replication in ScGT1 cells [Tran, 2010; Bolognesi, 2010]. In particular, we reported that the Phe-benzoquinone conjugate 1 exhibited remarkable anti-prion activity in a cellular model (EC50 = 0.87 M) [Tran, 2010]. This allowed us to propose that the benzoquinone might be considered a promising central core in the search for novel multitarget anti-prion compounds. Starting from these results, a further library featuring a central BQ nucleus, with two spacers in position 2 and 5 connected to two terminal moieties, was designed. Some of the library entries showed significant inhibition against PrPSc aggregation in ScGT1 cell line. Notably, 6-chloro-1,2,3,4-tetrahydroacridine 2 displayed an EC50 of 0.17 μM, which was lower than that of the reference compound quinacrine. More importantly, 2 possessed the capability to contrast prion fibril formation and oxidative stress, together with a low cytotoxicity [Bongarzone, 2010]. These results validate our design rationale as a viable strategy for the identification of novel lead compounds with more than one activity against prion diseases