Publication
Article Metrics
Citations
Online attention
Manno-epi-cyclophellitols enable activity-based protein profiling of human α-mannosidases and discovery of new golgi mannosidase II inhibitors
Authors:
Zachary
Armstrong
(The University of York)
,
Chi-Lin
Kuo
(Leiden University)
,
Daniël
Lahav
(Leiden University)
,
Bing
Liu
(Leiden University)
,
Rachel
Johnson
(The University of York)
,
Thomas J. M.
Beenakker
(Leiden University)
,
Casper
De Boer
(Leiden University)
,
Chung-Sing
Wong
(Leiden University)
,
Erwin R.
Van Rijssel
(Leiden University)
,
Marjoke F.
Debets
(Leiden University)
,
Bogdan I.
Florea
(Leiden University)
,
Colin
Hissink
(Leiden University)
,
Rolf G.
Boot
(Leiden University)
,
Paul P.
Geurink
(Leiden University Medical Centre)
,
Huib
Ovaa
(Leiden University Medical Centre)
,
Mario
Van Der Stelt
(Leiden University)
,
Gijsbert M.
Van Der Marel
(Leiden University)
,
Jeroen D. C.
Codée
(Leiden University)
,
Johannes M. F. G.
Aerts
(Leiden University)
,
Liang
Wu
(The University of York)
,
Herman S.
Overkleeft
(Leiden University)
,
Gideon
Davies
(The University of York)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Journal Of The American Chemical Society
State:
Published (Approved)
Published:
July 2020
Diamond Proposal Number(s):
18598
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.
Journal Keywords: Rodent models; Inhibitors; Inhibition; Peptides and proteins; Probes
Subject Areas:
Chemistry,
Biology and Bio-materials,
Medicine
Instruments:
I03-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
Added On:
20/07/2020 09:53
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)