Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Mimicking nature with synthetic macromolecules capable of recognition

Abstract

Nature has, through billions of years of evolution, assembled a multitude of polymeric macromolecules capable of exquisite molecular recognition. This functionality arises from the precise control exerted over their biosynthesis that results in key residues being anchored in the appropriate positions to interact with target substrates. Developing 'wholly synthetic' macromolecular analogues that can mimic this behaviour presents a considerable challenge to chemists, who lack the 'biological machinery' used in nature to assemble polymers with such precision. In addressing this challenge, familiar chemical concepts, such as combinatorial methods and supramolecular interactions, have been adapted for application in the macromolecular arena. Working from a limited set of residues, synthetic macromolecules have been produced that display surprisingly high binding affinities towards target proteins, even possessing useful in vivo activities. These observations are all the more surprising when one considers the heterogeneity inherent within these synthetic macromolecular receptors, and provoke intriguing questions regarding our assumptions about the design of receptors.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A summary of the three main approaches to the development of macromolecular receptors.
Figure 2: Exploiting multivalency in the production of polymeric receptors for arginine-rich proteins.
Figure 3: A 'catch-and release' system for lysozyme, designed by Shea and co-workers28.
Figure 4: Polymer-scaffolded dynamic combinatorial libraries (PS-DCLs) present a new route to the generation of macromolecular receptors.
Figure 5: Sequence-adaptive peptide nucleic acids, as reported by Ghadiri and colleagues53.

Similar content being viewed by others

References

  1. Stites, W. E. Protein−protein interactions: interface structure, binding thermodynamics, and mutational analysis. Chem. Rev. 97, 1233–1250 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Piletsky, S. A., Turner, N. W. & Laitenberger, P. Molecularly imprinted polymers in clinical diagnostics — future potential and existing problems. Med. Eng. Phys. 28, 971–977 (2006).

    Article  PubMed  Google Scholar 

  3. Yin, H. & Hamilton, A. D. Strategies for targeting protein-protein interactions with synthetic agents. Angew. Chem. Int. Ed. 44, 4130–4163 (2005).

    Article  CAS  Google Scholar 

  4. Arkin, M. R. & Wells, J. A. Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nature Rev. Drug. Discov. 3, 301–317 (2004).

    Article  CAS  Google Scholar 

  5. Carlmark, A., Hawker, C., Hult, A. & Malkoch, M. New methodologies in the construction of dendritic materials. Chem. Soc. Rev. 38, 352–362 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Wulff, G. & Sarhan, A. Use of polymers with enzyme-analogous structures for resolution of racemates. Angew. Chem. Int. Ed. Engl. 11, 341 (1972).

    CAS  Google Scholar 

  7. Wulff, G., Vesper, W., Grobe-Einsler, R. & Sarhan, A. Enzyme-analogue built polymers, 4. On the synthesis of polymers containing chiral cavities and their use for the resolution of racemates. Makromol. Chem. 178, 2799–2816 (1977).

    Article  CAS  Google Scholar 

  8. Haupt, K. & Mosbach, K. Molecularly imprinted polymers and their use in biomimetic sensors. Chem. Rev. 100, 2495–2504 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Alexander, C. et al. Molecular imprinting science and technology: a survey of the literature for the years up to and including 2003. J. Mol. Recognit. 19, 106–180 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Ye, L. & Mosbach, K. Molecular imprinting: synthetic materials as substitutes for biological antibodies and receptors. Chem. Mater. 20, 859–868 (2008).

    Article  CAS  Google Scholar 

  11. Wulff, G. Molecular imprinting in cross-linked materials with the aid of molecular templates— a way towards artificial antibodies. Angew. Chem. Int. Ed. Engl. 34, 1812–1832 (1995).

    Article  CAS  Google Scholar 

  12. Hoshino, Y. et al. Recognition, neutralization, and clearance of target peptides in the bloodstream of living mice by molecularly imprinted polymer nanoparticles: a plastic antibody. J. Am. Chem. Soc. 132, 6644–6645 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hoshino, Y. et al. The rational design of a synthetic polymer nanoparticle that neutralizes a toxic peptide in vivo. Proc. Natl Acad. Sci. USA 109, 33–38 (2012).

    Article  PubMed  Google Scholar 

  14. Lee, S-H. et al. Engineered synthetic polymer nanoparticles as IgG affinity ligands. J. Am. Chem. Soc. 134, 15765–15772 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yonamine, Y., Hoshino, Y. & Shea, K. J. ELISA-mimic screen for synthetic polymer nanoparticles with high affinity to target proteins. Biomacromolecules 13, 2952–2957 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mammen, M., Choi, S-K. & Whitesides, G. M. Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew. Chem. Int. Ed. 37, 2754–2794 (1998).

    Article  Google Scholar 

  17. Lees, W. J., Spaltenstein, A., Kingery-Wood, J. E. & Whitesides, G. M. Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza A virus: multivalency and steric stabilization of particulate biological systems. J. Med. Chem. 37, 3419–3433 (1994).

    Article  CAS  PubMed  Google Scholar 

  18. Mortell, K. H., Gingras, M. & Kiessling, L. L. Synthesis of cell agglutination inhibitors by aqueous ring-opening metathesis polymerization. J. Am. Chem. Soc. 116, 12053–12054 (1994).

    Article  CAS  Google Scholar 

  19. Shea, K. J., Spivak, D. A. & Sellergren, B. Polymer complements to nucleotide bases. Selective binding of adenine derivatives to imprinted polymers. J. Am. Chem. Soc. 115, 3368–3369 (1993).

    Article  CAS  Google Scholar 

  20. Umpleby, R. J. II et al. Characterization of the heterogeneous binding site affinity distributions in molecularly imprinted polymers. J. Chromatog. B 804, 141–149 (2004).

    Article  CAS  Google Scholar 

  21. Jung, G. Combinatorial Chemistry (Wiley-VCH, 1999).

    Book  Google Scholar 

  22. Kshirsagar, T. High-throughput Lead Optimization in Drug Discovery (Taylor & Francis 2008).

    Book  Google Scholar 

  23. Whitby, L. R. & Boger, D. L. Comprehensive peptidomimetic libraries targeting protein–protein interactions. Acc. Chem. Res. 45, 1698–1709 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rensing, S., Arendt, M., Springer, A., Grawe, T. & Schrader, T. Optimization of a synthetic arginine receptor. Systematic tuning of noncovalent interactions. J. Org. Chem. 66, 5814–5821 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Renner, C., Piehler, J. & Schrader, T. Arginine- and lysine-specific polymers for protein recognition and immobilization. J. Am. Chem. Soc. 128, 620–628 (2005).

    Article  CAS  Google Scholar 

  26. Koch, S. J., Renner, C., Xie, X. & Schrader, T. Tuning linear copolymers into protein-specific hosts. Angew. Chem. Int. Ed. 45, 6352–6355 (2006).

    Article  CAS  Google Scholar 

  27. Zeng, Z. et al. Synthetic polymer nanoparticle–polysaccharide interactions: a systematic study. J. Am. Chem. Soc. 134, 2681–2690 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yoshimatsu, K. et al. Temperature-responsive “catch and release” of proteins by using multifunctional polymer-based nanoparticles. Angew. Chem. Int. Ed. 51, 2405–2408 (2012).

    Article  CAS  Google Scholar 

  29. Corbett, P. T. et al. Dynamic combinatorial chemistry. Chem. Rev. 106, 3652–3711 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Reek, J. N. H. & Otto, S. Dynamic Combinatorial Chemistry (Wiley-VCH, 2010).

    Book  Google Scholar 

  31. Rowan, S. J., Cantrill, S. J., Cousins, G. R. L., Sanders, J. K. M. & Stoddart, J. F. Dynamic covalent chemistry. Angew. Chem. Int. Ed. 41, 898–952 (2002).

    Article  Google Scholar 

  32. Furlan, R. L. E., Cousins, G. R. L. & Sanders, J. K. M. Molecular amplification in a dynamic combinatorial library using non-covalent interactions. Chem. Commun. 1761–1762 (2000).

  33. Cousins, G. R. L., Furlan, R. L. E., Ng, Y. F., Redman, J. E. & Sanders, J. K. M. Identification and isolation of a receptor for N-methyl alkylammonium salts: molecular amplification in a pseudo-peptide dynamic combinatorial library. Angew. Chem. Int. Ed. 40, 423–428 (2001).

    Article  CAS  Google Scholar 

  34. Furlan, R. L. E., Ng, Y-F., Otto, S. & Sanders, J. K. M. A new cyclic pseudopeptide receptor for Li+ from a dynamic combinatorial library. J. Am. Chem. Soc. 123, 8876–8877 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Otto, S., Furlan, R. L. E. & Sanders, J. K. M. Selection and amplification of hosts from dynamic combinatorial libraries of macrocyclic disulfides. Science 297, 590–593 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Furlan, R. L. E., Ng, Y-F., Cousins, G. R. L., Redman, J. E. & Sanders, J. K. M. Molecular amplification in a dynamic system by ammonium cations. Tetrahedron 58, 771–778 (2002).

    Article  CAS  Google Scholar 

  37. Roberts, S. L., Furlan, R. L. E., Cousins, G. R. L. & Sanders, J. K. M. Simultaneous selection, amplification and isolation of a pseudo-peptide receptor by an immobilised N-methyl ammonium ion template. Chem. Commun. 938–939 (2002).

  38. Roberts, S. L., Furlan, R. L. E., Otto, S. & Sanders, J. K. M. Metal-ion induced amplification of three receptors from dynamic combinatorial libraries of peptide-hydrazones. Org. Biomol. Chem. 1, 1625–1633 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Klein, J. M. et al. A remarkably flexible and selective receptor for Ba2+ amplified from a hydrazone dynamic combinatorial library. Chem. Commun. 47, 3371–3373 (2011).

    Article  CAS  Google Scholar 

  40. Beeren, S. R. & Sanders, J. K. M. Ferrocene-amino acid macrocycles as hydrazone-based receptors for anions. Chem. Sci. 2, 1560–1567 (2011).

    Article  CAS  Google Scholar 

  41. Cheeseman, J. D. et al. Amplification of screening sensitivity through selective destruction: theory and screening of a library of carbonic anhydrase inhibitors. J. Am. Chem. Soc. 124, 5692–5701 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Corbett, A. D., Cheeseman, J. D., Kazlauskas, R. J. & Gleason, J. L. Pseudodynamic combinatorial libraries: a receptor-assisted approach for drug discovery. Angew. Chem. Int. Ed. 43, 2432–2436 (2004).

    Article  CAS  Google Scholar 

  43. Shi, B., Stevenson, R., Campopiano, D. J. & Greaney, M. F. Discovery of glutathione S-transferase inhibitors using dynamic combinatorial chemistry. J. Am. Chem. Soc. 128, 8459–8467 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Bhat, V. T. et al. Nucleophilic catalysis of acylhydrazone equilibration for protein-directed dynamic covalent chemistry. Nature Chem. 2, 490–497 (2010).

    Article  CAS  Google Scholar 

  45. Clipson, A. J. et al. Bivalent enzyme inhibitors discovered using dynamic covalent chemistry. Chem. Eur. J. 18, 10562–10570 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Karan, C. & Miller, B. L. RNA-selective coordination complexes identified via dynamic combinatorial chemistry. J. Am. Chem. Soc. 123, 7455–7456 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. McNaughton, B. R., Gareiss, P. C. & Miller, B. L. Identification of a selective small-molecule ligand for HIV-1 frameshift-inducing stem-loop RNA from an 11,325 member resin bound dynamic combinatorial library. J. Am. Chem. Soc. 129, 11306–11307 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Gareiss, P. C. et al. Dynamic combinatorial selection of molecules capable of inhibiting the (CUG) repeat RNA−MBNL1 interaction in vitro: discovery of lead compounds targeting myotonic dystrophy (DM1). J. Am. Chem. Soc. 130, 16254–16261 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fulton, D. A. Dynamic combinatorial libraries constructed on polymer scaffolds. Org. Lett. 10, 3291–3294 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Mahon, C. S., Jackson, A. W., Murray, B. S. & Fulton, D. A. Templating a polymer-scaffolded dynamic combinatorial library. Chem. Commun. 47, 7209–7211 (2011).

    Article  CAS  Google Scholar 

  51. Mahon, C. S., Jackson, A. W., Murray, B. S. & Fulton, D. A. Investigating templating within polymer-scaffolded dynamic combinatorial libraries. Polym. Chem. 4, 368–377 (2013).

    Article  CAS  Google Scholar 

  52. Mahon, C. S. & Fulton, D. A. Templation-induced re-equilibration in polymer-scaffolded dynamic combinatorial libraries leads to enhancements in binding affinities. Chem. Sci. 4, 3661–3666 (2013).

    Article  CAS  Google Scholar 

  53. Ura, Y., Beierle, J. M., Leman, L. J., Orgel, L. E. & Ghadiri, M. R. Self-assembling sequence-adaptive peptide nucleic acids. Science 325, 73–77 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Robertson, M. P. & Joyce, G. F. The origins of the RNA world. Cold Spring Harb. Perspect. Biol. 4, a003608 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Skene, W. G. & Lehn, J-M. P. Dynamers: polyacylhydrazone reversible covalent polymers, component exchange, and constitutional diversity. Proc. Natl Acad. Sci. USA 101, 8270–8275 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lehn, J. Dynamers: dynamic molecular and supramolecular polymers. Aust. J. Chem. 63, 611–623 (2010).

    Article  CAS  Google Scholar 

  57. Levrand, B., Ruff, Y., Lehn, J-M. & Herrmann, A. Controlled release of volatile aldehydes and ketones by reversible hydrazone formation — “classical” profragrances are getting dynamic. Chem. Commun. 2965–2967 (2006).

  58. Ono, T., Fujii, S., Nobori, T. & Lehn, J-M. Optodynamers: expression of color and fluorescence at the interface between two films of different dynamic polymers. Chem. Commun. 4360–4362 (2007).

  59. Ruff, Y. & Lehn, J-M. Glycodynamers: fluorescent dynamic analogues of polysaccharides. Angew. Chem. Int. Ed. 47, 3556–3559 (2008).

    Article  CAS  Google Scholar 

  60. Folmer-Andersen, J. F. & Lehn, J-M. Thermoresponsive dynamers: thermally induced, reversible chain elongation of amphiphilic poly(acylhydrazones). J. Am. Chem. Soc. 133, 10966–10973 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Moore, J. S. & Zimmerman, N. W. “Masterpiece” copolymer sequences by targeted equilibrium-shifting. Org. Lett. 2, 915–918 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Hoshino, Y. et al. Affinity purification of multifunctional polymer nanoparticles. J. Am. Chem. Soc. 132, 13648–13650 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Besenius, P., Cormack, P. A. G., Ludlow, R. F., Otto, S. & Sherrington, D. C. Polymer-supported cationic templates for molecular recognition of anionic hosts in water. Chem. Commun. 2809–2811 (2008).

  64. Besenius, P. et al. Tailored polymer-supported templates in dynamic combinatorial libraries: simultaneous selection, amplification and isolation of synthetic receptors. Chem. Eur. J. 14, 9006–9019 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Corbett, P. T., Otto, S. & Sanders, J. K. M. What are the limits to the size of effective dynamic combinatorial libraries? Org. Lett. 6, 1825–1827 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Corbett, P. T., Otto, S. & Sanders, J. K. M. Correlation between host–guest binding and host amplification in simulated dynamic combinatorial libraries. Chem. Eur. J. 10, 3139–3143 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Corbett, P. T., Sanders, J. K. M. & Otto, S. Competition between receptors in dynamic combinatorial libraries: Amplification of the fittest? J. Am. Chem. Soc. 127, 9390–9392 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Carnall, J. M. A. et al. Mechanosensitive self-replication driven by self-organization. Science 327, 1502–1506 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Xu, S. & Giuseppone, N. Self-duplicating amplification in a dynamic combinatorial library. J. Am. Chem. Soc. 130, 1826–1827 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Nguyen, R., Allouche, L., Buhler, E. & Giuseppone, N. Dynamic combinatorial evolution within self-replicating supramolecular assemblies. Angew. Chem. Int. Ed. 48, 1093–1096 (2009).

    Article  CAS  Google Scholar 

  71. Sadownik, J. W. & Philp, D. A simple synthetic replicator amplifies itself from a dynamic reagent pool. Angew. Chem. Int. Ed. 47, 9965–9970 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge the financial support of the Engineering and Physical Sciences Research Council (EP/G066507/1).

Author information

Authors and Affiliations

Authors

Contributions

C.S.M. and D.A.F. contributed equally to the writing of this article.

Corresponding author

Correspondence to David A. Fulton.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mahon, C., Fulton, D. Mimicking nature with synthetic macromolecules capable of recognition. Nature Chem 6, 665–672 (2014). https://doi.org/10.1038/nchem.1994

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1994

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing