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.

许多重要的生物分子过程需要蛋白质识别DNA表面特征。模仿这些特征的分子可能会充当诱饵并干扰与药理或治疗相关的蛋白质-DNA相互作用。尽管已经描述了天然存在的模拟DNA的蛋白质，但模仿双链DNA电荷表面的合成可调分子尚不为人所知。在这里，我们报道了折叠成单螺旋构象并在与B-DNA的磷酸部分匹配的位置显示带负电荷残基的双螺旋阵列的芳香族低酰胺的设计，合成和结构表征。这些分子能够抑制几种具有非序列选择性DNA结合特性的酶，包括拓扑异构酶1和HIV-1整合酶，大概是通过特定的折叠蛋白与蛋白质的相互作用，而序列选择酶却没有受到抑制。这种模块化的，可合成的DNA模拟物为设计新型的蛋白质与DNA相互作用的抑制剂提供了一个多功能的平台。