Synthesis of (3S,4S,5S)-trihydroxylpiperidine derivatives as enzyme stabilizers to improve therapeutic enzyme activity in Fabry patient cell lines

Huang Yi Li, Jay Der Lee, Chiao Wen Chen, Ying Chieh Sun, Wei Chieh Cheng*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

A series of 3S,4S,5S-trihydroxylated piperidines bearing structural diversity at C-2 or C-6 positions has been synthesized and tested to determine their ability to stabilize the activity of recombinant human α-Galactosidase A (rh-α-Gal A). Hit molecules were identified by rapid inhibitory activity screening, and then further investigated for their ability to protect this enzyme from thermo-induced denaturation and enhance its activity in Fabry patient cell lines. Our study resulted in the identification of a new class of small molecules as enzyme stabilizers for the potential treatment of Fabry disease. Of these, stabilizer 21 was the most effective, showing a 12-fold increase in rh-α-Gal A activity in Fabry disease cell lines.

Original languageEnglish
Pages (from-to)626-634
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume144
DOIs
Publication statusPublished - 2018 Jan 20

Keywords

  • Combinatorial chemistry
  • Enzyme stabilizer
  • Fabry disease
  • Iminosugar
  • Lysosomal α-galactosidase
  • Trihydroxylated piperidine

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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