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Exploring the divalent effect in fucosidase inhibition with stereoisomeric pyrrolidine dimers

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Author(s)

  • Audrey Hottin
  • Daniel W. Wright
  • Elena Moreno-Clavijo
  • Antonio J. Moreno-Vargas
  • Gideon J. Davies
  • Jean Bernard Behr

Department/unit(s)

Publication details

JournalOrganic and Biomolecular Chemistry
DateAccepted/In press - 25 Apr 2016
DateE-pub ahead of print - 25 Apr 2016
DatePublished (current) - 2016
Issue number20
Volume14
Number of pages10
Pages (from-to)4718-4727
Early online date25/04/16
Original languageEnglish

Abstract

Multi-valent inhibitors offer promise for the enhancement of therapeutic compounds across a range of chemical and biological processes. Here, a significant increase in enzyme-inhibition potencies was observed with a dimeric iminosugar-templated fucosidase inhibitor (IC50 = 0.108 μM) when compared to its monovalent equivalent (IC50 = 2.0 μM). Such a gain in binding is often attributed to a "multivalent effect" rising from alternative recapture of the scaffolded binding epitopes. The use of control molecules such as the meso analogue (IC50 = 0.365 μM) or the enantiomer (IC50 = 569 μM), as well as structural analysis of the fucosidase-inhibitor complex, allowed a detailed analysis of the possible mechanism of action, at the molecular level. Here, the enhanced binding affinity of the dimer over the monomer can be attributed to additional interactions in non-catalytic sites as also revealed in the 3-D structure of a bacterial fucosidase inhibitor complex.

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© Royal Society of Chemistry 2016. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details

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