2,5-Dideoxy-2,5-imino-d-altritol as a new class of pharmacological chaperone for Fabry disease

Atsushi Kato*, Yukiko Yamashita, Shinpei Nakagawa, Yuriko Koike, Isao Adachi, Jackie Hollinshead, Robert J. Nash, Kyoko Ikeda, Naoki Asano

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Chromatographic separation of the extract from roots of Adenophora triphylla resulted in the isolation of two pyrrolidines, six piperidines, and two piperidine glycosides. The structures of new iminosugars were elucidated by spectroscopic methods as 2,5-dideoxy-2,5-imino-d-altritol (DIA) (2), β-1-C-butenyl-1-deoxygalactonojirimycin (8), 2,3-dideoxy-β-1-C-ethyl-1-deoxygalactonojirimycin (9), and 6-O-β-d-glucopyranosyl-2,3-dideoxy-β-1-C-ethyl-1-deoxygalactonojirimycin (10). β-1-C-Butyl-1-deoxygalactonojirimycin (7) and compound 8 were found to be better inhibitors of α-galactosidase than N-butyl-1-deoxygalactonojirimycin. The present work elucidated that DIA was a powerful competitive inhibitor of human lysosome α-galactosidase A (α-Gal A) with a Ki value of 0.5 μM. Furthermore, DIA improved the thermostability of α-Gal A in vitro and increased intracellular α-Gal A activity by 9.6-fold in Fabry R301Q lymphoblasts after incubation for 3 days. These experimental results suggested that DIA would act as a specific pharmacological chaperone to promote the smooth escape from the endoplasmic reticulum (ER) quality control system and to accelerate transport and maturation of the mutant enzyme.

Original languageEnglish
Pages (from-to)3790-3794
Number of pages5
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number11
DOIs
StatePublished - 2010/06/01

Keywords

  • 2,5-Dideoxy-2,5-imino-d-altritol
  • Adenophora triphylla
  • Glycosidase inhibitor
  • Pharmacological chaperone
  • α-Galactosidase A

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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