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From the same journal

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

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Published copy (DOI)

Author(s)

  • Chi Lin Kuo
  • Daniël Lahav
  • Bing Liu
  • Rachel Johnson
  • Thomas J.M. Beenakker
  • Casper De Boer
  • Chung Sing Wong
  • Erwin R. Van Rijssel
  • Marjoke F. Debets
  • Bogdan I. Florea
  • Colin Hissink
  • Rolf G. Boot
  • Paul P. Geurink
  • Huib Ovaa
  • Mario Van Der Stelt
  • Gijsbert M. Van Der Marel
  • Jeroen D.C. Codée
  • Johannes M.F.G. Aerts
  • Herman S. Overkleeft

Department/unit(s)

Publication details

JournalJournal of the American Chemical Society
DateE-pub ahead of print - 1 Jul 2020
DatePublished (current) - 29 Jul 2020
Issue number30
Volume142
Number of pages9
Pages (from-to)13021-13029
Early online date1/07/20
Original languageEnglish

Abstract

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.

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