A biomimetic receptor for glucose

Abstract

Specific molecular recognition is routine for biology, but has proved difficult to achieve in synthetic systems. Carbohydrate substrates are especially challenging, because of their diversity and similarity to water, the biological solvent. Here we report a synthetic receptor for glucose, which is biomimetic in both design and capabilities. The core structure is simple and symmetrical, yet provides a cavity which almost perfectly complements the all-equatorial β-pyranoside substrate. The receptor’s affinity for glucose, at Ka ~ 18,000 M−1, compares well with natural receptor systems. Selectivities also reach biological levels. Most other saccharides are bound approximately 100 times more weakly, while non-carbohydrate substrates are ignored. Glucose-binding molecules are required for initiatives in diabetes treatment, such as continuous glucose monitoring and glucose-responsive insulin. The performance and tunability of this system augur well for such applications.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Design of glucose receptor 2.
Fig. 2: Synthetic route to receptor 2.
Fig. 3: Evidence for binding of 2 to glucose 10.
Fig. 4: Substrates and affinities for receptor 2.

Data availability

The data supporting this study are provided in the Supplementary Information and are also available from the authors upon reasonable request.

References

  1. 1.

    Persch, E., Dumele, O. & Diederich, F. Molecular recognition in chemical and biological systems. Angew. Chem. Int. Ed. 54, 3290–3327 (2015).

    CAS  Article  Google Scholar 

  2. 2.

    Schrader, T. & Hamilton, A. D. Functional Synthetic Receptors (Wiley-VCH, Weinheim, 2005).

    Google Scholar 

  3. 3.

    Smith, B. D. (ed.) Synthetic Receptors for Biomolecules: Design Principles and Applications (Royal Societyof Chemistry, Cambridge, 2015).

  4. 4.

    Kolesnichenko, I. V. & Anslyn, E. V. Practical applications of supramolecular chemistry. Chem. Soc. Rev. 46, 2385–2390 (2017).

    CAS  Article  Google Scholar 

  5. 5.

    Ma, X. & Zhao, Y. Biomedical applications of supramolecular systems based on host-guest interactions. Chem. Rev. 115, 7794–7839 (2015).

    CAS  Article  Google Scholar 

  6. 6.

    Oshovsky, G. V., Reinhoudt, D. N. & Verboom, W. Supramolecular chemistry in water. Angew. Chem. Int. Ed. 46, 2366–2393 (2007).

    CAS  Article  Google Scholar 

  7. 7.

    Kataev, E. A. & Muller, C. Recent advances in molecular recognition in water: artificial receptors and supramolecular catalysis. Tetrahedron 70, 137–167 (2014).

    CAS  Article  Google Scholar 

  8. 8.

    Davis, A. P. Supramolecular chemistry: sticking to sugars. Nature 464, 169–170 (2010).

    CAS  Article  Google Scholar 

  9. 9.

    Sun, X. L. & James, T. D. Glucose sensing in supramolecular chemistry. Chem. Rev. 115, 8001–8037 (2015).

    CAS  Article  Google Scholar 

  10. 10.

    Wu, Q., Wang, L., Yu, H. J., Wang, J. J. & Chen, Z. F. Organization of glucose-responsive systems and their properties. Chem. Rev. 111, 7855–7875 (2011).

    CAS  Article  Google Scholar 

  11. 11.

    Davis, A. P. & Wareham, R. S. Carbohydrate recognition through noncovalent interactions: a challenge for biomimetic and supramolecular chemistry. Angew. Chem. Int. Ed. 38, 2978–2996 (1999).

    CAS  Article  Google Scholar 

  12. 12.

    Draganov, A. et al. in Synthetic Receptors for Biomolecules: Design Principles and Applications (ed. Smith, B. D.) 177–203 (Royal Society of Chemistry, Cambridge, 2015).

  13. 13.

    Solis, D. et al. A guide into glycosciences: how chemistry, biochemistry and biology cooperate to crack the sugar code. Biochim. Biophys. Acta. Gen. Subj. 1850, 186–235 (2015).

    CAS  Article  Google Scholar 

  14. 14.

    Ambrosi, M., Cameron, N. R. & Davis, B. G. Lectins: tools for the molecular understanding of the glycocode. Org. Biomol. Chem. 3, 1593–1608 (2005).

    CAS  Article  Google Scholar 

  15. 15.

    Toone, E. J. Structure and energetics of protein-carbohydrate complexes. Curr. Opin. Struct. Biol. 4, 719–728 (1994).

    CAS  Article  Google Scholar 

  16. 16.

    Klein, E., Crump, M. P. & Davis, A. P. Carbohydrate recognition in water by a tricyclic polyamide receptor. Angew. Chem. Int. Ed. 44, 298–302 (2005).

    CAS  Article  Google Scholar 

  17. 17.

    Ferrand, Y., Crump, M. P. & Davis, A. P. A synthetic lectin analog for biomimetic disaccharide recognition. Science 318, 619–622 (2007).

    CAS  Article  Google Scholar 

  18. 18.

    Ke, C., Destecroix, H., Crump, M. P. & Davis, A. P. A simple and accessible synthetic lectin for glucose recognition and sensing. Nat. Chem. 4, 718–723 (2012).

    CAS  Article  Google Scholar 

  19. 19.

    Mooibroek, T. J. et al. A threading receptor for polysaccharides. Nat. Chem. 8, 69–74 (2016).

    CAS  Article  Google Scholar 

  20. 20.

    Rios, P. et al. Synthetic receptors for high-affinity recognition of O-GlcNAc derivatives. Angew. Chem. Int. Ed. 55, 3387–3392 (2016).

    CAS  Article  Google Scholar 

  21. 21.

    Rios, P. et al. Enantioselective carbohydrate recognition by synthetic lectins in water. Chem. Sci. 8, 4056–4061 (2017).

    CAS  Google Scholar 

  22. 22.

    Sookcharoenpinyo, B., Klein, E., Ke, C. & Davis, A. P. Nucleoside recognition by oligophenyl-based synthetic lectins. Supramol. Chem. 25, 650–655 (2013).

    CAS  Article  Google Scholar 

  23. 23.

    Peck, E. M. et al. Rapid macrocycle threading by a fluorescent dye-polymer conjugate in water with nanomolar affinity. J. Am. Chem. Soc. 137, 8668–8671 (2015).

    CAS  Article  Google Scholar 

  24. 24.

    James, T. D., Phillips, M. D. & Shinkai, S. Boronic Acids in Saccharide Recognition (RSC, Cambridge, 2006).

    Google Scholar 

  25. 25.

    Hennrich, G. & Anslyn, E. V. 1,3,5-2,4,6-Functionalized, facially segregated benzenes - exploitation of sterically predisposed systems in supramolecular chemistry. Chem. Eur. J. 8, 2218–2224 (2002).

    CAS  Article  Google Scholar 

  26. 26.

    Francesconi, O., Ienco, A., Moneti, G., Nativi, C. & Roelens, S. A self-assembled pyrrolic cage receptor specifically recognizes beta-glucopyranosides. Angew. Chem. Int. Ed. 45, 6693–6696 (2006).

    CAS  Article  Google Scholar 

  27. 27.

    Mazik, M. Recent developments in the molecular recognition of carbohydrates by artificial receptors. RSC Adv. 2, 2630–2642 (2012).

    CAS  Article  Google Scholar 

  28. 28.

    Asensio, J. L., Arda, A., Canada, F. J. & Jimenez-Barbero, J. Carbohydrate-aromatic interactions. Acc. Chem. Res. 46, 946–954 (2013).

    CAS  Article  Google Scholar 

  29. 29.

    Meyer, E. A., Castellano, R. K. & Diederich, F. Interactions with aromatic rings in chemical and biological recognition. Angew. Chem. Int. Ed. 42, 1210–1250 (2003).

    CAS  Article  Google Scholar 

  30. 30.

    Barwell, N. P., Crump, M. P. & Davis, A. P. A synthetic lectin for beta-glucosyl. Angew. Chem. Int. Ed. 48, 7673–7676 (2009).

    CAS  Article  Google Scholar 

  31. 31.

    Basu, A. et al. Continuous glucose monitor interference with commonly prescribed medications: a pilot study. J. Diabetes Sci. Technol. 11, 936–941 (2017).

    CAS  Article  Google Scholar 

  32. 32.

    Quiocho, F. A. Protein-carbohydrate interactions: basic molecular features. Pure Appl. Chem. 61, 1293–1306 (1989).

    CAS  Article  Google Scholar 

  33. 33.

    Zhao, F. Q. & Keating, A. F. Functional properties and genomics of glucose transporters. Curr. Genomics 8, 113–128 (2007).

    CAS  Article  Google Scholar 

  34. 34.

    Shoham, J., Inbar, M. & Sachs, L. Differential toxicity on normal transformed cells in-vitro and inhibition of tumour development in-vivo by Concanavalin-A. Nature 227, 1244–1246 (1970).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank the Bristol Chemical Synthesis Doctoral Training Centre for a studentship to R.A.T., funded jointly by Ziylo and the Engineering and Physical Sciences Research Council (EP/G036764/1).

Author information

Affiliations

Authors

Contributions

R.A.T. designed and carried out the synthetic route to receptor 2. M.G.O. and J.V.M. assisted in optimisation of the synthesis of compound 7. R.A.T. performed and analysed the binding studies, with assistance from T.S.C. and L.C. in some cases. R.A.T. and L.C. prepared the biological media. R.A.T. and M.P.C. were responsible for the structural NMR work, and H.L. performed the cytotoxicity studies. A.P.D. designed the receptor and directed the study. The paper was written by A.P.D. with input from the other authors.

Corresponding author

Correspondence to Anthony P. Davis.

Ethics declarations

Competing interests

While this paper was under consideration, Ziylo Ltd was purchased by Novo Nordisk with a view to the development of glucose-responsive insulin. A new company Carbometrics was created to collaborate with Ziylo and explore other applications. A.P.D. was a director and shareholder of Ziylo, and is now a director and shareholder of Carbometrics. T.S.C., L.C., J.V.M. and M.G.O. were employees of Ziylo, J.V.M. and M.G.O. are now employees of Carbometrics.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Synthesis and characterization of receptor 2; synthetic methods, NMR spectra, stability and toxicity. Details of binding studies; methods and media, summary of binding results, binding data and analyses. Details of modelling studies

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tromans, R.A., Carter, T.S., Chabanne, L. et al. A biomimetic receptor for glucose. Nature Chem 11, 52–56 (2019). https://doi.org/10.1038/s41557-018-0155-z

Download citation

Further reading