Characterising the selectivity of ER α-glucosidase inhibitors

Sarah O'keefe, Quentin P Roebuck, Izumi Nakagome, Shuichi Hirono, Atsushi Kato, Robert Nash, Stephen High

Research output: Contribution to journalArticlepeer-review


The endoplasmic reticulum (ER) contains both α-glucosidases and α-mannosidases which process the N-linked oligosaccharides of newly synthesised glycoproteins and thereby facilitate polypeptide folding and glycoprotein quality control. By acting as structural mimetics, iminosugars can selectively inhibit these ER localised α-glycosidases, preventing N-glycan trimming and providing a molecular basis for their therapeutic applications. In this study, we investigate the effects of a panel of nine iminosugars on the actions of ER luminal α-glucosidase I and α-glucosidase II. Using ER microsomes to recapitulate authentic protein N-glycosylation and oligosaccharide processing, we identify five iminosugars that selectively inhibit N-glycan trimming. Comparison of their inhibitory activities in ER microsomes against their effects on purified ER α-glucosidase II, suggests that 3,7a-diepi-alexine acts as a selective inhibitor of ER α-glucosidase I. The other active iminosugars all inhibit α-glucosidase II and, having identified 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) as the most effective of these compounds, we use in silico modelling to understand the molecular basis for this enhanced activity. Taken together, our work identifies the C-3 substituted pyrrolizidines casuarine and 3,7a-diepi-alexine as promising “second-generation” iminosugar inhibitors.
Original languageEnglish
Early online date12 Apr 2019
Publication statusPublished - 2019


  • endoplasmic reticulum
  • glucose trimming
  • iminosugar inhibitors
  • N-linked glycosylation


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