Synthesis and screening of a library of Lewisx deoxyfluoro-analogues reveals differential recognition by glycan-binding partners
Glycan-mediated interactions play a crucial role in biology and medicine, influencing signalling, immune responses, and disease pathogenesis. However, the use of glycans in biosensing and diagnostics is limited by cross-reactivity, as certain glycan motifs can be recognised by multiple biologically distinct protein receptors. To address this specificity challenge, we report the enzymatic synthesis of a 150-member library of site-specifically fluorinated Lewis<sup>x</sup> analogues ('glycofluoroforms') using naturally occurring enzymes and fluorinated monosaccharides. Subsequent incorporation of a subset of these glycans into nanoparticles or a microarray revealed a striking spectrum of distinct binding intensities across different proteins that recognise Lewis<sup>x</sup>. Notably, we show that for two proteins with unique binding sites for Lewis<sup>x</sup>, glycofluoroforms exhibited enhanced binding to one protein, whilst reduced binding to the other, with selectivity governed by fluorination patterns. We finally showcase the potential diagnostic utility of this approach in glycofluoroform-mediated bacterial toxin detection by lateral flow.
Authors
- Harriet S. Chidwick
- Matthew Balmforth (ORCID: https://orcid.org/0000-0003-2651-9428)
- Ryan McBerney (ORCID: https://orcid.org/0000-0002-4631-0800)
- Hélène Ledru
- David E. Wheatley (ORCID: https://orcid.org/0000-0002-5075-5554)
- Michael E. Webb (ORCID: https://orcid.org/0000-0003-3574-4686)
- Bruno Linclau (ORCID: https://orcid.org/0000-0001-8762-0170)
- Jean-Baptiste Vendeville (ORCID: https://orcid.org/0000-0002-5790-6968)
- Tessa Keenan (ORCID: https://orcid.org/0000-0003-2466-6918)
- Martin A. Fascione (ORCID: https://orcid.org/0000-0002-0066-4419)
- James Finnigan (ORCID: https://orcid.org/0000-0002-8514-784X)
- Stuart L. Warriner (ORCID: https://orcid.org/0000-0002-7589-6011)
- Tomasz P. Kamiński (ORCID: https://orcid.org/0000-0003-4823-3797)
- Sabine L. Flitsch (ORCID: https://orcid.org/0000-0003-3974-646X)
- W. Bruce Turnbull (ORCID: https://orcid.org/0000-0002-7352-0360)
- Fabio Parmeggiani (ORCID: https://orcid.org/0000-0001-5861-9269)
- M. Carmen Galán (ORCID: https://orcid.org/0000-0001-7307-2871)
- Antonio Di Maio (ORCID: https://orcid.org/0000-0002-2740-9098)
- Andrea Marchesi (ORCID: https://orcid.org/0000-0003-0493-9835)
- Matthew I. Gibson (ORCID: https://orcid.org/0000-0002-8297-1278)
- Wengang Chai (ORCID: https://orcid.org/0000-0003-2977-5347)
- Ten Feizi (ORCID: https://orcid.org/0000-0001-6495-0329)
- Kristian Hollingsworth (ORCID: https://orcid.org/0000-0003-3163-7111)
- Sarah‐Jane Richards (ORCID: https://orcid.org/0000-0003-3888-9290)
- Alexandra Tamasanu (ORCID: https://orcid.org/0009-0007-5253-242X)
- Yan Liu (ORCID: https://orcid.org/0000-0002-2566-6867)
- Kun Huang (ORCID: https://orcid.org/0000-0003-0269-2963)
- Carl S. Young (ORCID: https://orcid.org/0009-0006-5195-2388)
Institutions
- University of Leeds (GB)
- University of Manchester (GB)
- Ghent University (BE)
- University of Bristol (GB)
- University of Warwick (GB)
- Prozomix (United Kingdom) (GB)
- Institute of Structural and Molecular Biology (GB)
- University of Southampton (GB)
- Imperial College London (GB)
- University of York (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1038/s41467-024-51081-7
- Citations
- 10
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- March of Dimes Foundation
- Wellcome Trust
- Imperial College London
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council