Defining the potential of aglycone modifications for affinity/selectivity enhancement against medically relevant lectins: Synthesis, activity screening, and HSQC-Based NMR Analysis

Subhash R. Rauthu, Tze Chieh Shiao, Sabine André, Michelle C. Miller, Élodie Madej, Kevin H. Mayo, Hans Joachim Gabius, René Roy

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The emerging significance of lectins for pathophysiological processes provides incentive for the design of potent inhibitors. To this end, systematic assessment of contributions to affinity and selectivity by distinct types of synthetic tailoring of glycosides is a salient step, here taken for the aglyconic modifications of two disaccharide core structures. Firstly we report the synthesis of seven N-linked-lactosides and of eight O-linked N-acetyllactosamines, each substituted with a 1,2,3-triazole unit, prepared by copper-catalyzed azide-alkyne cycloaddition (CuAAC). The totally regioselective β-D-(1→4) galactosylation of a 6-O-TBDPSi-protected N-acetylglucosamine acceptor provided efficient access to the N-acetyllactosamine precursor. The resulting compounds were then systematically tested for lectin reactivity in two binding assays of increasing biorelevance (inhibition of lectin binding to a surface-presented glycoprotein and to cell surfaces). As well as a plant toxin, we also screened the relative inhibitory potential with adhesion/growth-regulatory galectins (total of eight proteins). This type of modification yielded up to 2.5-fold enhancement for prototype proteins, with further increases for galectins-3 and -4. Moreover, the availability of15N-labeled proteins and full assignments enabled1H15N HSQC-based measurements for human galectins-1, -3, and -7 against p-nitrophenyl lactopyrano-side, a frequently tested standard inhibitor containing an aromatic aglycone. The measurements confirmed the highest affinity against galectin-3 and detected chemical shift differences in its hydrophobic core upon ligand binding, besides common alterations around the canonical contact site for the lactoside residue. What can be accomplished in terms of affinity/selectivity by this type of core extension having been determined, the applied combined strategy should be instrumental for proceeding with defining structure-activity correlations at other bioinspired sites in glycans and beyond the tested lectin types.

Original languageEnglish (US)
Pages (from-to)126-139
Number of pages14
JournalChemBioChem
Volume16
Issue number1
DOIs
StatePublished - Jan 2 2015

Bibliographical note

Publisher Copyright:
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords

  • Galectins
  • Glycoproteins
  • Lactose
  • Lectins
  • Structure-activity relationships

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