Tight-binding inhibition of jack bean α-mannosidase by glycoimidazole clusters
Tight-binding inhibition of jack bean α-mannosidase by glycoimidazole clusters
The best multivalent effects observed in glycosidase inhibition have been achieved so far with jack bean α-mannosidase (JBα-man) using iminosugar clusters based on weakly binding mismatching active-site-directed inhibiting epitopes (inhitopes) in the d-gluco series. Here, we synthesize and evaluate as JBα-man inhibitors a series of mono- to 14-valent glycoimidazoles with inhitopes displaying inhibition values up to the range of hundreds of nMs to study the impact of inhitope affinity on the multivalent effect. The most potent inhibitor of the series, a 14-valent mannoimidazole derivative, inhibits JBα-man with a nanomolar Ki value (2 ± 0.5 nM) and binding enhancements observed are, at best, relatively small (up to 25-fold on a valency-corrected basis). The results of this study support the fact that JBα-man-inhitope affinity and the strength of the inhibitory multivalent effect evolve in the opposite direction. The major impact of the glycoimidazole-based inhitope is found on the binding scenario; most of the synthesized mannoimidazole clusters as well as a 14-valent glucoimidazole derivative prove to be tight binding inhibitors of JBα-man.
5801-5817
Pichon, Maëva M.
84bb0e1a-a659-4e77-9dbd-6b61d2fa2a31
Stauffert, Fabien
77e7c9e7-5828-4683-97e0-41381cc06842
Bodlenner, Anne
a97ef344-4e55-47b5-8f7d-90799d615519
Compain, Philippe
adb871dd-570e-4b25-96f2-cd0462627f52
21 June 2019
Pichon, Maëva M.
84bb0e1a-a659-4e77-9dbd-6b61d2fa2a31
Stauffert, Fabien
77e7c9e7-5828-4683-97e0-41381cc06842
Bodlenner, Anne
a97ef344-4e55-47b5-8f7d-90799d615519
Compain, Philippe
adb871dd-570e-4b25-96f2-cd0462627f52
Pichon, Maëva M., Stauffert, Fabien, Bodlenner, Anne and Compain, Philippe
(2019)
Tight-binding inhibition of jack bean α-mannosidase by glycoimidazole clusters.
Organic and Biomolecular Chemistry, 17 (23), .
(doi:10.1039/c9ob00826h).
Abstract
The best multivalent effects observed in glycosidase inhibition have been achieved so far with jack bean α-mannosidase (JBα-man) using iminosugar clusters based on weakly binding mismatching active-site-directed inhibiting epitopes (inhitopes) in the d-gluco series. Here, we synthesize and evaluate as JBα-man inhibitors a series of mono- to 14-valent glycoimidazoles with inhitopes displaying inhibition values up to the range of hundreds of nMs to study the impact of inhitope affinity on the multivalent effect. The most potent inhibitor of the series, a 14-valent mannoimidazole derivative, inhibits JBα-man with a nanomolar Ki value (2 ± 0.5 nM) and binding enhancements observed are, at best, relatively small (up to 25-fold on a valency-corrected basis). The results of this study support the fact that JBα-man-inhitope affinity and the strength of the inhibitory multivalent effect evolve in the opposite direction. The major impact of the glycoimidazole-based inhitope is found on the binding scenario; most of the synthesized mannoimidazole clusters as well as a 14-valent glucoimidazole derivative prove to be tight binding inhibitors of JBα-man.
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Accepted/In Press date: 21 May 2019
e-pub ahead of print date: 21 May 2019
Published date: 21 June 2019
Identifiers
Local EPrints ID: 433927
URI: http://eprints.soton.ac.uk/id/eprint/433927
ISSN: 1477-0520
PURE UUID: c8cbdff1-2a11-4129-a20b-65abfa27e288
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Date deposited: 06 Sep 2019 16:30
Last modified: 17 Mar 2024 12:31
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Author:
Fabien Stauffert
Author:
Anne Bodlenner
Author:
Philippe Compain
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