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.

  • Article
  • Published:

Single helically folded aromatic oligoamides that mimic the charge surface of double-stranded B-DNA

Nature Chemistry volume 10, pages 511–518 (2018)Cite this article

Subjects

Abstract

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.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: DNA mimic design.
Fig. 2: Structural characterization.
Fig. 3: Enzyme inhibition.
Fig. 4: Inhibition of Top1 and HIV-IN by polyanions.
Fig. 5: Foldamer–protein binding.
Fig. 6: Cell-based assays.

Similar content being viewed by others

References

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

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

    CAS  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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

  1. Ivan Huc

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

Authors and Affiliations

  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

Authors
  1. Krzysztof Ziach
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Céline Chollet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vincent Parissi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Panchami Prabhakaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mathieu Marchivie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Valentina Corvaglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Partha Pratim Bose
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Katta Laxmi-Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Frédéric Godde
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean-Marie Schmitter
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stéphane Chaignepain
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Philippe Pourquier
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ivan Huc
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Ivan Huc.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Supplementary Information

Supplementary Tables, Figures, Data and Methods

Life Sciences Reporting Summary

Supplementary Video 1

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

Crystallographic data

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

Crystallographic data

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

Crystallographic data

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

Crystallographic data

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ziach, K., Chollet, C., Parissi, V. et al. Single helically folded aromatic oligoamides that mimic the charge surface of double-stranded B-DNA. Nature Chem 10, 511–518 (2018). https://doi.org/10.1038/s41557-018-0018-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-018-0018-7

This article is cited by

Search

Advanced 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