Peptidomimetic-Based Multidomain Targeting Offers Critical Evaluation of Aβ Structure and Toxic Function

Sunil Kumar, Anja Henning-Knechtel, Mazin Magzoub, Andrew D. Hamilton

Research output: Contribution to journalArticle

Abstract

The prevailing hypothesis stipulates that the preamyloid oligomers of Aβ are the main culprits associated with the onset and progression of Alzheimer's disease (AD), which has prompted efforts to search for therapeutic agents with the ability to inhibit Aβ oligomerization and amyloidogenesis. However, clinical progress is impeded by the limited structural information about the neurotoxic oligomers. To address this issue, we have adopted a synthetic approach, where a library of oligopyridylamide-based small molecules was tested against various microscopic events implicated in the self-assembly of Aβ. Two oligopyridylamides bind to different domains of Aβ and affect distinct microscopic events in Aβ self-assembly. The study lays the foundations for a dual recognition strategy to simultaneously target different domains of Aβ for further improvement in antiamyloidogenic activity. The data demonstrate that one of the most effective oligopyridylamides forms a high affinity complex with Aβ, which sustains the compound's activity in cellular milieu. The oligopyridylamide was able to rescue cells when introduced 24 h after the incubation of Aβ. The rescue of Aβ toxicity is potentially a consequence of the colocalization of the oligopyridylamide with Aβ. The synthetic tools utilized here provide a straightforward strategic framework to identify a range of potent antagonists of Aβ-mediated toxic functions. This approach could be a powerful route to the design of candidate drugs for various amyloid diseases that have so far proven to be "untargetable".

Original languageEnglish (US)
Pages (from-to)6562-6574
Number of pages13
JournalJournal of the American Chemical Society
Volume140
Issue number21
DOIs
StatePublished - May 30 2018

ASJC Scopus subject areas

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

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