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Iterative design of a helically folded aromatic oligoamide sequence for the selective encapsulation of fructose

Nature Chemistry volume 7, pages 334–341 (2015)Cite this article

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Abstract

The ab initio design of synthetic molecular receptors for a specific biomolecular guest remains an elusive objective, particularly for targets such as monosaccharides, which have very close structural analogues. Here we report a powerful approach to produce receptors with very high selectivity for specific monosaccharides and, as a demonstration, we develop a foldamer that selectively encapsulates fructose. The approach uses an iterative design process that exploits the modular structure of folded synthetic oligomer sequences in conjunction with molecular modelling and structural characterization to inform subsequent refinements. Starting from a first-principles design taking size, shape and hydrogen-bonding ability into account and using the high predictability of aromatic oligoamide foldamer conformations and their propensity to crystallize, a sequence that binds to β-D-fructopyranose in organic solvents with atomic-scale complementarity was obtained in just a few iterative modifications. This scheme, which mimics the adaptable construction of biopolymers from a limited number of monomer units, provides a general protocol for the development of selective receptors.

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Figure 1: Schematic representation of structure-based iterative evolution of a foldamer sequence.
Figure 2: Host–guest components and assembly.
Figure 3: Spectroscopic assessment of host–guest association.
Figure 4: Crystal structures of complexes of first-generation capsule P-1.
Figure 5: Sugar-binding modes with first-generation capsule P-1.
Figure 6: Iterative receptor design.

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Acknowledgements

This work was supported by the Agence Nationale de la Recherche (project no. ANR-09-BLAN-0082-01, post-doctoral fellowship to N.C.), by the Conseil Interprofessionnel du Vin de Bordeaux (predoctoral fellowship to G.L.) and by the European Research Council under the European Union's Seventh Framework Programme (grant agreement no. ERC-2012-AdG-320892, post-doctoral fellowship to G.L.). The authors thank A. Kendhale and C. Blum for preliminary investigations on the preparation of ‘H’ monomers, the IR-RMN-THC Fr3050 CNRS for high-field NMR time, J-L. Ferrer for beamtime and help during data collection on FIP-BM30A at the European Synchrotron Radiation Facility and P. Nowak (University of Gröningen) for calculations using the DCLSim software.

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Authors and Affiliations

  1. University of Bordeaux, CBMN (UMR 5248), Institut Européen de Chimie et Biologie, 2 rue Escarpit, Pessac, 33600, France

    Nagula Chandramouli, Yann Ferrand, Guillaume Lautrette, Michel Laguerre & Ivan Huc

  2. CNRS, CBMN (UMR 5248), France

    Nagula Chandramouli, Yann Ferrand, Guillaume Lautrette, Michel Laguerre & Ivan Huc

  3. University of Bordeaux, IECB (UMS 3033), Institut Européen de Chimie et Biologie, 2 rue Escarpit, Pessac, 33600, France

    Brice Kauffmann

  4. CNRS, IECB (UMS 3033), France

    Brice Kauffmann

  5. INSERM, IECB (US 001), France

    Brice Kauffmann

  6. University of Bordeaux, ARNA (U 869), Institut Européen de Chimie et Biologie, 2 rue Escarpit, Pessac, 33600, France

    Cameron David Mackereth

  7. INSERM, ARNA (U 869), France

    Cameron David Mackereth

  8. University of Nantes, CEISAM (UMR 6230), Faculté des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, Nantes Cedex 3, 44322, France

    Didier Dubreuil

  9. CNRS, CEISAM (UMR 6230), France

    Didier Dubreuil

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  1. Nagula Chandramouli
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Contributions

N.C. and G.L. synthesized all new compounds. N.C., Y.F., G.L. and C.D.M. carried out solution studies. B.K. collected X-ray data and solved the crystal structures. M.L. performed modelling studies. I.H., D.D. and Y.F. designed the study. I.H., Y.F. and C.D.M. co-wrote the manuscript. All authors discussed the results and commented on the manuscript. N.C. and Y.F. contributed equally to this work.

Corresponding author

Correspondence to Ivan Huc.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary information (PDF 10488 kb)

Supplementary movie

Supplementary movie (MP4 16206 kb)

Supplementary information

Crystallographic data for host-guest complex 1⊃β-7a (CIF 3372 kb)

Supplementary information

Crystallographic data for host-guest complex 1⊃α-8a (CIF 6224 kb)

Supplementary information

Crystallographic data for host-guest complex 1⊃β-9a (CIF 12211 kb)

Supplementary information

Crystallographic data for host-guest complex 1⊃α-13a (CIF 7306 kb)

Supplementary information

Crystallographic data for host-guest complex 3⊃β-7a (CIF 3543 kb)

Supplementary information

Crystallographic data for host-guest complex 5⊃β-7a (CIF 3072 kb)

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Chandramouli, N., Ferrand, Y., Lautrette, G. et al. Iterative design of a helically folded aromatic oligoamide sequence for the selective encapsulation of fructose. Nature Chem 7, 334–341 (2015). https://doi.org/10.1038/nchem.2195

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