Immobilized Amyloid Hexamer Fragments to Map Active Sites of Amyloid-Targeting Chemicals

Illhwan Cho, Soljee Yoon, Sunghyun Park, Seung Woo Hong, Eunjung Cho, Eosu Kim, Hye Yun Kim, Young Soo Kim

Research output: Contribution to journalArticlepeer-review

Abstract

As amyloid-β (Aβ) peptide is considered a biomarker and pathological culprit of Alzheimer's disease, Aβ-targeting compounds have been investigated for diagnostics development and drug discovery of the disorder. Unlike amyloid plaque targeting agents, such as clinically available amyloid radiotracers intercalating into the β-sheet structures of the aggregates, monomer and oligomer targeting chemicals are difficult to develop, as the transient and polymorphic nature of these peptides impedes their structural understanding. Here, we report a mapping approach to explore targeting residues of Aβ-imaging probes and Aβ-regulating drug candidates by utilizing a set of fragmented Aβ hexamers immobilized on a 96-well microplate in combination with fluorescent full-length Aβ for on-plate aggregation. To evaluate the mapping potential of the peptide plate, we tested previously reported fluorescent imaging agents (CRANAD-28, bis-ANS), aggregation inhibitors (curcumin, scyllo-inositol), and aggregate dissociators (necrostatin-1, sunitinib) targeting Aβ. Our approach enabled mechanistic understanding of compounds targeting nonfibrillar Aβ on an interacting sequence level.

Original languageEnglish
Pages (from-to)9-18
Number of pages10
JournalACS Chemical Neuroscience
Volume14
Issue number1
DOIs
Publication statusAccepted/In press - 2022

Bibliographical note

Funding Information:
This research was supported by the Korea Health Technology R&D Project (Grant Number: HU21C0161, Y.K.) through the Korea Health Industry Development Institute (KHIDI) and Korea Dementia Research Center (KDRC), and Mid-Career Researcher Program (Grant Number: NRF-2021R1A2C2093916, Y.K.; NRF-2021R1A2C1013247, H.Y.K.), and Basic Science Research Program (Grant Number: NRF-2018R1A6A1A03023718, Y.K. and H.Y.K.) through the National Research Foundation of Korea (NRF), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea. This research was also supported by Amyloid Solution and POSCO Science Fellowship of POSCO TJ Park Foundation.

Publisher Copyright:
© 2022 American Chemical Society.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

Fingerprint

Dive into the research topics of 'Immobilized Amyloid Hexamer Fragments to Map Active Sites of Amyloid-Targeting Chemicals'. Together they form a unique fingerprint.

Cite this