α-Helix Mimetics as Modulators of Aß Self-Assembly.

ABSTRACT

A key molecular species in Alzheimer's disease (AD) is the Aß42 alloform of Aß 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 Aß42 is predominantly disordered but samples α-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 α-helical mimetics was designed to target the central α-helix subdomain of Aß (Aß13-26). A tripyridylamide, ADH-41, was identified as one of the most potent antagonists of Aß fibrillation. Amyloid-assembly kinetics, transmission electron microscopy (TEM), and atomic force microscopy (AFM) show that ADH-41 wholly suppresses the aggregation of Aß at a substoichiometric dose. Dot blot and ELISA assays demonstrate the inhibition of the putative neurotoxic Aß oligomers. ADH-41 targets Aß 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 Aß. Spectroscopic studies using NMR and CD confirm induction of α-helicity in Aß 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 Aß probably by modulating the Aß conformation into a fiber incompetent structure. Overall, we speculate that ADH-41 directs Aß into off-pathway structures, and thereby alters various solution based functions of Aß. Cell-based assays to assess the effect of ADH-41 on Aß are underway and will be presented in due course.