Numerous essential biomolecular processes require the recognition of DNA surface features by proteins. Molecules mimicking these features could potentially act as decoys and interfere with pharmacologically or therapeutically relevant protein–DNA interactions. Although naturally occurring DNA-mimicking proteins have been described, synthetic tunable molecules that mimic the charge surface of double-stranded DNA are not known. Here, we report the design, synthesis and structural characterization of aromatic oligoamides that fold into single helical conformations and display a double helical array of negatively charged residues in positions that match the phosphate moieties in B-DNA. These molecules were able to inhibit several enzymes possessing non-sequence-selective DNA-binding properties, including topoisomerase 1 and HIV-1 integrase, presumably through specific foldamer–protein interactions, whereas sequence-selective enzymes were not inhibited. Such modular and synthetically accessible DNA mimics provide a versatile platform to design novel inhibitors of protein–DNA interactions.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

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


  1. 1.

    Nielsen, P. E., Egholm, M., Berg, R. H. & Buchardt, O. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 254, 1497–1500 (1991).

  2. 2.

    Koshkin, A. A. et al. LNA (locked nucleic acids): synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition. Tetrahedron 54, 3607–3630 (1998).

  3. 3.

    Obika, S. et al. Synthesis of 2′-O,4′-C-methyleneuridine and -cytidine. Novel bicyclic nucleosides having a fixed C3′-endo sugar puckering. Tetrahedron Lett. 38, 8735–8738 (1997).

  4. 4.

    Veedu, R. K. & Wengel, J. Locked nucleic acids: promising nucleic acid analogs for therapeutic applications. Chem. Biodiv. 7, 536–542 (2010).

  5. 5.

    Nielsen, P. E. Nucleic Acid Backbone Structure Variations: Peptide Nucleic Acids (Wiley, Chichester, 2014).

  6. 6.

    Rohs, R. et al. Origins of specificity in protein–DNA recognition. Annu. Rev. Biochem. 79, 233–269 (2010).

  7. 7.

    Luscombe, N. M., Austin, S. E., Berman, H. M. & Thornton, J. M. An overview of the structures of protein–DNA complexes. Genome Biol. 1, reviews001.1 (2000).

  8. 8.

    Wang, H.-C., Ho, C.-H., Hsu, K.-C., Yang, J.-M. & Wang, A. H.-J. DNA mimic proteins: functions, structures, and bioinformatic analysis. Biochemistry 53, 2865–2874 (2014).

  9. 9.

    Dryden, D. T. F. DNA mimicry by proteins and the control of enzymatic activity on DNA. Trends Biotechnol. 24, 378–382 (2006).

  10. 10.

    Yüksel, D., Bianco, P. R. & Kumar, K. De novo design of protein mimics of B-DNA. Mol. BioSyst. 12, 169–177 (2016).

  11. 11.

    Chenoweth, D. M., Poposki, J. A., Marques, M. A. & Dervan, P. B. Programmable oligomers targeting 5′-GGGG-3′ in the minor groove of DNA and NF-κB binding inhibition. Bioorg. Med. Chem. 15, 759–770 (2007).

  12. 12.

    Bremer, R. E., Baird, E. E. & Dervan, P. B. Inhibition of major-groove-binding-proteins by pyrrole-imidazole polyamides with an Arg-Pro-Arg positive patch. Chem. Biol. 5, 119–133 (1998).

  13. 13.

    Ducani, C., Leczkowska, A., Hodges, N. J. & Hannon, H. J. Noncovalent DNA-binding metallo-supramolecular cylinders prevent DNA transactions in vitro. Angew. Chem. Int. Ed. 49, 8942–8945 (2010).

  14. 14.

    Brabec, V. et al. Metallohelices with activity against cisplatin-resistant cancer cells; does the mechanism involve DNA binding? Chem. Sci. 4, 4407–4416 (2013).

  15. 15.

    Maher, L. J. III, Wold, B. & Dervan, P. B. Inhibition of DNA binding proteins by oligonucleotide-directed triple helix formation. Science 245, 725–730 (1989).

  16. 16.

    Azzarito, V., Long, K., Murphy, N. S. & Wilson, A. J. Inhibition of α-helix-mediated protein–protein interactions using designed molecules. Nat. Chem. 5, 161–173 (2013).

  17. 17.

    Jayatunga, M. K. P., Thompson, S. & Hamilton, A. D. α-Helix mimetics: outwards and upwards. Bioorg. Med. Chem. Lett. 24, 717–724 (2014).

  18. 18.

    Johnson, L. M. & Gellmann, S. H. α-Helix mimicry with α/β-peptides. Methods Enzymol. 523, 407–429 (2013).

  19. 19.

    Koert, U., Harding, M. M. & Lehn, J.-M. DNH deoxyribonucleohelicates: self assembly of oligonucleosidic double-helical metal complexes. Nature 346, 339–342 (1990).

  20. 20.

    Conrad, H. E. Heparin-Binding Proteins (Academic, San Diego, 1998).

  21. 21.

    Monien, B. H. & Desai, U. R. Antithrombin activation by nonsulfated, non-polysaccharide organic polymer. J. Med. Chem. 48, 1269–1273 (2005).

  22. 22.

    Rodriguez, R. J. Polyphosphate present in DNA preparations from filamentous fungal species of Collectrichum inhibits restriction endonucleases and other enzymes. Anal. Biochem. 209, 291–297 (1993).

  23. 23.

    Jiang, H., Léger, J.-M. & Huc, I. Aromatic delta-peptides. J. Am. Chem. Soc. 125, 3448–3449 (2003).

  24. 24.

    Dolain, C. et al. Solution structure of quinoline- and pyridine-derived oligoamide foldamers. Chem. Eur. J. 11, 6135–6144 (2005).

  25. 25.

    Qi, T. et al. Solvent dependence of helix stability in aromatic oligoamide foldamers. Chem. Commun. 48, 6337–6339 (2012).

  26. 26.

    Sánchez-García, D. et al. Nanosized hybrid oligoamide foldamers: aromatic templates for the folding of multiple aliphatic units. J. Am. Chem. Soc. 131, 8642–8648 (2009).

  27. 27.

    Baptiste, B., Douat-Casassus, C., Laxmi-Reddy, K., Godde, F. & Huc, I. Solid phase synthesis of aromatic oligoamides: application to helical water-soluble foldamers. J. Org. Chem. 75, 7175–7185 (2010).

  28. 28.

    Qi, T., Deschrijver, T. & Huc, I. Large-scale and chromatography-free synthesis of an octameric quinoline-based aromatic amide helical foldamer. Nat. Protoc. 8, 693–708 (2013).

  29. 29.

    Liu, Z., Abramyan, A. M. & Pophristic, V. Helical arylamide foldamer: structure prediction by molecular dynamics simulations. New J. Chem. 39, 3229–3240 (2015).

  30. 30.

    Hu, X. et al. Optimizing side chains for crystal growth from water: a case study of aromatic amide foldamers. Chem. Sci. 8, 3741–3749 (2017).

  31. 31.

    Hu, X., Dawson, S. J., Nagaoka, A. & Huc, I. Solid-phase synthesis of water-soluble helically folded hybrid α-amino acid/quinoline oligoamides. J. Org. Chem. 81, 1137–1150 (2016).

  32. 32.

    Lu, H. et al. Ionic polypeptides with unusual helical stability. Nat. Commun. 2, 206 (2011).

  33. 33.

    Tumey, L. N. et al. The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors. Bioorg. Med. Chem. Lett. 15, 277–281 (2005).

  34. 34.

    Redinbo, M. R., Stewart, L., Kuhn, P., Champoux, J. J. & Hol, W. G. J. Crystal structure of human topoisomerase I in covalent and noncolvalent complexes with DNA. Science 279, 1504–1513 (1998).

  35. 35.

    Hare, S., Gupta, S. S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232–236 (2010).

  36. 36.

    Cheng, C., Kussie, P., Pavletich, N. & Shuman, S. Conservation of structure and mechanism between eukaryotic topoisomerase I and site-specific recombinases. Cell 92, 841–850 (1998).

  37. 37.

    Hazuda, D. J. et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287, 646–650 (2000).

  38. 38.

    Lesbats, P. et al. In vitro initial attachment of HIV-1 integrase to viral ends: control of the DNA specific interaction by the oligomerization state. Nucleic Acids Res. 36, 7043–7058 (2008).

  39. 39.

    Hsiang, Y. H., Lihou, M. G. & Liu, L. F. Arrest of replication forks by drug-stabilized topoisomerase I–DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res. 49, 5077–5082 (1989).

  40. 40.

    Ishii, K. et al. Mechanism of inhibition of mammalian DNA topoisomerase I by heparin. Biochem. J. 241, 111–119 (1987).

  41. 41.

    Xiong., S., Zhang, L. & He, Q. Y. Fractionation of proteins by heparin chromatography. Methods Biol. Mol. 424, 213–221 (2008).

  42. 42.

    Maertens, G. et al. EDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J. Biol. Chem. 278, 33528–33539 (2003).

  43. 43.

    Demeulemeester, J., De Rijck, J., Gijsbers, R. & Debyser, Z. Retroviral integration: site matters: mechanisms and consequences of retroviral integration site selection. Bioessays 37, 1202–1214 (2015).

  44. 44.

    Ciolkowski, M. L., Fang, M. M. & Lund, M. E. A surface plasmon resonance method for detecting multiple modes of DNA–ligand interactions. J. Pharm. Biomed. Anal. 22, 1037–1045 (2000).

  45. 45.

    Lo, Y. S., Tseng, W. H., Chuang, C. Y. & Hou, M. H. The structural basis of actinomycin D-binding induces nucleotide flipping out, a sharp bend and a left-handed twist in CGG triplet repeats. Nucleic Acids Res. 41, 4284–4294 (2013).

  46. 46.

    Nguyen, B., Tanious, F. A. & Wilson, W. D. Biosensor-surface plasmon resonance: Quantitative analysis of small molecule–nucleic acid interactions. Methods 42, 150–161 (2007).

  47. 47.

    Bailly, C. et al. Sequence-specific minor groove binding by bis-benzimidazoles: water molecules in ligand recognition. Nucleic Acids Res. 31, 1514–1524 (2003).

Download references


This work was supported by the Agence Nationale de la Recherche (project no. ANR-11-BS07-013-01 and project RETROSelect, jcjc2011 program), by the French National Research Agency against AIDS (ANRS, AO2016), by SIDACTION (AO2016, VIH20160721002), by the European Union under the Seventh Framework Programme (grant agreements nos. ERC-2012-AdG-320892 and PEOPLE-2011-IEF-300948) and by the Ligue contre le Cancer (Comité Languedoc Roussillon). The authors thank Mr B. Kauffmann for assistance with crystallographic measurements and resolution, Mr J.-L. Ferrer for beam time and help during data collection on FIP BM30A at the ESRF, and Mr C. Di Primo and Ms L. Minder for assistance with SPR measurements. This work benefited from the facilities and expertise of the Biophysical and Structural Chemistry platform at IECB, CNRS UMS3033, INSERM US001, Bordeaux University, France.

Author information

Author notes

    • Ivan Huc

    Present address: Department of Pharmacy, Ludwig-Maximilians-Universität, München, Germany


  1. Univ. Bordeaux – CNRS – IPB, CBMN Laboratory (UMR5248), Institut Européen de Chimie et Biologie, Pessac, France

    • Krzysztof Ziach
    • , Céline Chollet
    • , Panchami Prabhakaran
    • , Valentina Corvaglia
    • , Partha Pratim Bose
    • , Katta Laxmi-Reddy
    • , Frédéric Godde
    • , Jean-Marie Schmitter
    • , Stéphane Chaignepain
    •  & Ivan Huc
  2. Univ. Bordeaux – CNRS, Laboratoire de Microbiologie Fondamentale et Pathogénicité (UMR 5234), Bordeaux, France

    • Vincent Parissi
  3. Univ. Bordeaux – CNRS, ICMCB (UPR9048), Pessac, France

    • Mathieu Marchivie
  4. INSERM U1194, Institut de Recherche en Cancérologie de Montpellier & Université de Montpellier, Montpellier, France

    • Philippe Pourquier


  1. Search for Krzysztof Ziach in:

  2. Search for Céline Chollet in:

  3. Search for Vincent Parissi in:

  4. Search for Panchami Prabhakaran in:

  5. Search for Mathieu Marchivie in:

  6. Search for Valentina Corvaglia in:

  7. Search for Partha Pratim Bose in:

  8. Search for Katta Laxmi-Reddy in:

  9. Search for Frédéric Godde in:

  10. Search for Jean-Marie Schmitter in:

  11. Search for Stéphane Chaignepain in:

  12. Search for Philippe Pourquier in:

  13. Search for Ivan Huc in:


K.Z. and C.C. contributed equally to this work. K.Z., P.Pr., V.C. and P.P.B. synthesized all new compounds. K.L.-R. synthesized earlier lipophilic versions of the DNA mimics that were critical to the design. K.Z. carried out NMR structural studies. C.C., V.P., S.C. and P.Po. carried out biological assays. M.M. resolved the crystal structures. I.H., V.P., F.G., J.-M.S., S.C. and P.Po. designed the study. I.H. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Ivan Huc.

Supplementary information

  1. Supplementary Information

    Supplementary Tables, Figures, Data and Methods

  2. Life Sciences Reporting Summary

  3. Supplementary Video 1

    A 3D animation of the solvent accessible surfaces of the structure of a DNA mimic compared to that of B-DNA

  4. Crystallographic data

    Crystallographic data Crystallographic data and Structure factors for Boc(mQQ4)8OBn; CCDC 1059495

  5. Crystallographic data

    Crystallographic data and Structure factors for Boc(mQQ4)8OTMSE;CCDC 1059497

  6. Crystallographic data

    Crystallographic data and Structure factors for Boc(mQQ4)16OBn; CCDC 1059493

  7. Crystallographic data

    Crystallographic data and Structure factors for Boc(mQQ5)4OBn CIF; CCDC 1059496

About this article

Publication history