α-Helix Mimetics as Modulators of Aβ Self-Assembly

Abstract

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

Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin

“…The oligopyridylamides form a network of intramolecular hydrogen bonds that stabilize a single conformation and project side chain functionalities from one face that correspond to the side chain residues of an α-helical conformation at i, i+3 (i+4), and i+7 72 . The use of these oligopyridylamides has been shown to effectively disrupt αhelix-mediated protein-protein interactions 73,74 . To disrupt the SRM/SET-I helical interaction, we synthesized a library of oligopyridylamides by designing the surface functionalities complementary to the side chain residues of the SRM helical interface ( Figure 6A and 6B).…”

“…The monomers for the preparation of the oligopyridylamides were synthesized according to a previously published method 73 . Following the monomer synthesis, chain elongation of pyridylamides was achieved using iterative amide coupling between oligopyridylamines and monomeric-pyridylacids using 2-chloro-1-methylpyridinium iodide (Mukaiyama's reagent) followed by reduction of the nitro groups.…”

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

“…We previously reported the use of oligopyridylamide-based α-helix mimetics to effectively modulate self-assembly of the amyloid-β peptide (Aβ) 20,21 and islet amyloid polypeptide (IAPP) 22 , which are associated with Alzheimer's disease (AD) and type II diabetes (T2D), respectively. α-helix mimetics are small molecules that imitate the topography of the most commonly occurring protein secondary structure, serving as effective antagonists of protein-protein interactions (PPIs) at the interaction interface 23,24 .…”

Alleviation of symptoms of Alzheimer's disease by diminishing Aβ neurotoxicity and neuroinflammation

“…The CD spectra of Ab42 were somewhat different from those of Ab40 possibly because Ab42 aggregated into brils more quickly than Ab40, which was consistent with previous reports. [43][44][45] The interactions of BIBA with the Zn 2+ -or Cu 2+ -induced Ab40 aggregates were further investigated by ESI-MS. As shown in Fig. 2D and E, no peaks assignable to Ab40 species or BIBA-Ab40 adducts are observed aer the co-incubation of Ab40, metal ions and BIBA (see Tables S2 and S3 †), suggesting that no covalent interactions occurred between BIBA and Ab40.…”