Characterizing the selectivity of ER α-glucosidase inhibitors.

Autor:	O'Keefe S; School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Roebuck QP; School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Nakagome I; School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan., Hirono S; School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan., Kato A; Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama, Japan., Nash R; PhytoQuest Ltd, Plas Gogerddan, Aberystwyth, Ceredigion, UK., High S; School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Jazyk:	angličtina
Zdroj:	Glycobiology [Glycobiology] 2019 Jul 01; Vol. 29 (7), pp. 530-542.
DOI:	10.1093/glycob/cwz029
Abstrakt:	The endoplasmic reticulum (ER) contains both α-glucosidases and α-mannosidases which process the N-linked oligosaccharides of newly synthesized glycoproteins and thereby facilitate polypeptide folding and glycoprotein quality control. By acting as structural mimetics, iminosugars can selectively inhibit these ER localized 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 modeling 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. (© The Author(s) 2019. Published by Oxford University Press.)
Databáze:	MEDLINE
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