Identification of α-Synuclein Proaggregator: Rapid Synthesis and Streamlining RT-QuIC Assays in Parkinson's Disease

Fumito Takada, Takahito Kasahara, Kentaro Otake, Takamitsu Maru, Masanori Miwa, Kei Muto, Minoru Sasaki, Yoshihiko Hirozane, Masato Yoshikawa*, Junichiro Yamaguchi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

We report the discovery of two compounds, TKD150 and TKD152, that promote the aggregation of α-synuclein (aSN) using a real-time quaking-induced conversion (RT-QuIC) assay to detect abnormal aSN. By utilizing a Pd-catalyzed C-H arylation of benzoxazole with iodoarenes and implementing a planar conformation to the design, we successfully identified TKD150 and TKD152 as proaggregators for aSN. In comparison to a previously reported proaggregator, PA86, the two identified compounds were able to promote aggregation of aSN at twice the rate. Application of TKD150 and TKD152 to the RT-QuIC assay will shorten the inherent lag time and may allow wider use of this assay in clinical settings for the diagnosis of α-synucleinopathy-related diseases.

Original languageEnglish
Pages (from-to)1421-1426
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume13
Issue number9
DOIs
Publication statusPublished - 2022 Sep 8

Keywords

  • C-H Arylation
  • RT-QuIC
  • proaggregator
  • α-synuclein

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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