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.
The authors declare no competing interests.
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Supplementary Tables, Figures, Data and Methods
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 and Structure factors for Boc(mQQ4)8OBn; CCDC 1059495
Crystallographic data and Structure factors for Boc(mQQ4)8OTMSE;CCDC 1059497
Crystallographic data and Structure factors for Boc(mQQ4)16OBn; CCDC 1059493
Crystallographic data and Structure factors for Boc(mQQ5)4OBn CIF; CCDC 1059496
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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
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