Loos Manuel, Xu Felix, Mandal Pradeep K, Chakrabortty Tulika, Douat Céline, Konrad David B, Cabbar Melis, Singer Johannes, Corvaglia Valentina, Carell Thomas, Huc Ivan
Department of Pharmacy Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, München, 81377, Germany.
Department of Chemistry Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, München, 81377, Germany.
Angew Chem Int Ed Engl. 2025 Jul 28;64(31):e202505273. doi: 10.1002/anie.202505273. Epub 2025 Jun 17.
A linker unit was designed and synthesized that can serve both as a hairpin turn in a DNA duplex and anchor point for an aromatic helical foldamer mimicking the shape and surface properties of B-DNA. Methods were developed to synthesize natural/non-natural chimeric molecules combining foldamer and DNA segments. The ability of the linker to position the foldamer helix and the duplex DNA so that their rims and grooves are in register, despite their completely different chemical nature, was demonstrated using single crystal X-ray diffraction, circular dichroism and molecular models. Bio-layer interferometry confirmed that artificial hairpin DNA duplexes keep their ability to bind to DNA binding proteins. The chimeric molecules may pave the way to competitive inhibitors of protein-DNA interactions involving sequence-selective DNA-binding proteins.
设计并合成了一种连接单元，它既可以作为DNA双链中的发夹结构，又可以作为模拟B-DNA形状和表面性质的芳香螺旋折叠体的锚定点。开发了合成结合折叠体和DNA片段的天然/非天然嵌合分子的方法。利用单晶X射线衍射、圆二色性和分子模型证明，尽管连接单元和折叠体螺旋以及双链DNA的化学性质完全不同，但连接单元能够将折叠体螺旋和双链DNA定位，使它们的边缘和凹槽对齐。生物层干涉术证实，人工发夹DNA双链保持了与DNA结合蛋白结合的能力。这些嵌合分子可能为涉及序列选择性DNA结合蛋白的蛋白质-DNA相互作用的竞争性抑制剂铺平道路。
