Manno-epi-cyclophellitols Enable Activity-Based Protein Profiling of Human α‑Mannosidases and Discovery of New Golgi Mannosidase II Inhibitors

Golgi mannosidase II (GMII) catalyzes the sequential hydrolysis of two mannosyl residues from GlcNAcMan5GlcNAc2 to produce GlcNAcMan3GlcNAc2, the precursor for all complex N-glycans, including the branched N-glycans associated with cancer. Inhibitors of GMII are potential cancer therapeutics, but th...

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Bibliographic Details
Published in:	Journal of the American Chemical Society Vol. 142; no. 30; pp. 13021 - 13029
Main Authors:	Armstrong, Zachary, Kuo, Chi-Lin, Lahav, Daniël, Liu, Bing, Johnson, Rachel, Beenakker, Thomas J. M, de Boer, Casper, Wong, Chung-Sing, van Rijssel, Erwin R, Debets, Marjoke F, Florea, Bogdan I, Hissink, Colin, Boot, Rolf G, Geurink, Paul P, Ovaa, Huib, van der Stelt, Mario, van der Marel, Gijsbert M, Codée, Jeroen D. C, Aerts, Johannes M. F. G, Wu, Liang, Overkleeft, Herman S, Davies, Gideon J
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 29-07-2020
Subjects:	Cyclohexanols - chemical synthesis Cyclohexanols - chemistry Cyclohexanols - pharmacology Drug Discovery Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Mannosidases - antagonists & inhibitors Mannosidases - metabolism Molecular Structure
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Summary:	Golgi mannosidase II (GMII) catalyzes the sequential hydrolysis of two mannosyl residues from GlcNAcMan5GlcNAc2 to produce GlcNAcMan3GlcNAc2, the precursor for all complex N-glycans, including the branched N-glycans associated with cancer. Inhibitors of GMII are potential cancer therapeutics, but their usefulness is limited by off-target effects, which produce α-mannosidosis-like symptoms. Despite many structural and mechanistic studies of GMII, we still lack a potent and selective inhibitor of this enzyme. Here, we synthesized manno-epi-cyclophellitol epoxide and aziridines and demonstrate their covalent modification and time-dependent inhibition of GMII. Application of fluorescent manno-epi-cyclophellitol aziridine derivatives enabled activity-based protein profiling of α-mannosidases from both human cell lysate and mouse tissue extracts. Synthesized probes also facilitated a fluorescence polarization-based screen for dGMII inhibitors. We identified seven previously unknown inhibitors of GMII from a library of over 350 iminosugars and investigated their binding modalities through X-ray crystallography. Our results reveal previously unobserved inhibitor binding modes and promising scaffolds for the generation of selective GMII inhibitors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0002-7863 1520-5126
DOI:	10.1021/jacs.0c03880