α-Helix Mimetics as Modulators of Aβ Self-Assembly

A key molecular species in Alzheimer's disease (AD) is the A beta(42) alloform of A beta peptide, which is dominant in the amyloid plaques deposited in the brains of AD patients. Recent studies have decisively demonstrated that the prefibrillar soluble oligomers are the neurotoxic culprits and are associated with the pathology of AD. Nascent A beta(42) is predominantly disordered but samples alpha-helical conformations covering residues 15-24 and 29-35 in the presence of micelles and structure-inducing solvents. In this report, a focused library of oligopyridylamide based alpha-helical mimetics was designed to target the central alpha-helix subdomain of A beta (A beta(13-26)). A tripyridylamide, ADH-41, was identified as one of the most potent antagonists of A beta fibrillation. Amyloid-assembly kinetics, transmission electron microscopy (TEM), and atomic force microscopy (AFM) show that ADH-41 wholly suppresses the aggregation of A beta at a substoichiometric dose. Dot blot and ELISA assays demonstrate the inhibition of the putative neurotoxic A beta oligomers. ADH-41 targets. A beta in a sequence and structure-specific manner, as it did not have any effect on the aggregation of islet amyloid polypeptide (IAPP), a peptide which shares sequence similarity with A beta. Spectroscopic studies using NMR and CD confirm induction of alpha-helicity in A beta mediated by ADH-41. Calorimetric and fluorescence titrations yielded binding affinity in the low micromolar range. ADH-41 was also effective at inhibiting the seed-catalyzed aggregation of A beta probably by modulating the A beta conformation into a fiber incompetent structure. Overall, we speculate that ADH-41 directs A beta into off-pathway structures, and thereby alters various solution based functions of A beta. Cell-based assays to assess the effect of ADH-41 on A beta are underway and will be presented in due course.