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.

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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


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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

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