α-Helix Mimetics as Modulators of Aβ Self-Assembly

Sunil Kumar, Andrew Hamilton

Research output: Contribution to journalArticle

Abstract

A key molecular species in Alzheimer's disease (AD) is the Aβ42 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 Aβ42 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 (Aβ13-26). 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.

Original languageEnglish (US)
Pages (from-to)5744-5755
Number of pages12
JournalJournal of the American Chemical Society
Volume139
Issue number16
DOIs
StatePublished - Apr 26 2017

Fingerprint

Self assembly
Modulators
Alzheimer Disease
Agglomeration
Oligomers
Amyloid
Peptides
Conformations
Assays
Islet Amyloid Polypeptide
Atomic Force Microscopy
Polypeptides
Amyloid Plaques
Brain Diseases
Micelles
Pathology
Transmission Electron Microscopy
Titration
Libraries
Seed

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

α-Helix Mimetics as Modulators of Aβ Self-Assembly. / Kumar, Sunil; Hamilton, Andrew.

In: Journal of the American Chemical Society, Vol. 139, No. 16, 26.04.2017, p. 5744-5755.

Research output: Contribution to journalArticle

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