Department of Biological Chemistry, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, 08034, Barcelona, Spain.
NMR Facility (IQAC-CSIC), Jordi Girona 18-26, 08034, Barcelona, Spain.
Angew Chem Int Ed Engl. 2020 Sep 21;59(39):17202-17206. doi: 10.1002/anie.202004745. Epub 2020 May 26.
Dynamic covalent chemistry combines in a single step the screening and synthesis of ligands for biomolecular recognition. In order to do that, a chemical entity is used as template within a dynamic combinatorial library of interconverting species, so that the stronger binders are amplified due to the efficient interaction with the target. Here we employed whole A549 living cells as template in a dynamic mixture of imines, for which amplification reflects the efficient and selective interaction with the corresponding extracellular matrix. The amplified polyamine showed strong interaction with the A549 extracellular matrix in on-cell NMR experiments, while combination of NMR, SPR, and molecular dynamics simulations in model systems provided insights on the molecular recognition event. Notably, our work pioneers the use of whole living cells in dynamic combinatorial chemistry, which paves the way towards the discovery of new bioactive molecules in a more biorelevant environment.
动态共价化学在一步中结合了生物分子识别配体的筛选和合成。为此，将一种化学实体用作动态组合文库中相互转化物种的模板，从而由于与靶标的有效相互作用而使更强的结合物得到放大。在这里，我们在动态亚胺混合物中使用整个 A549 活细胞作为模板，其中的放大反映了与相应细胞外基质的有效和选择性相互作用。在细胞内 NMR 实验中，放大的多胺与 A549 细胞外基质表现出强烈的相互作用，而在模型系统中结合 NMR、SPR 和分子动力学模拟则提供了分子识别事件的见解。值得注意的是，我们的工作开创了在动态组合化学中使用整个活细胞的先河，为在更具生物相关性的环境中发现新的生物活性分子铺平了道路。
