McAnany John D, Reichert John P, Miller Benjamin L
Department of Chemistry, University of Rochester, Rochester, NY 14642, United States.
Department of Biochemistry and Biophysics, University of Rochester, Rochester, NY 14642, United States.
Bioorg Med Chem. 2016 Sep 1;24(17):3940-3946. doi: 10.1016/j.bmc.2016.02.029. Epub 2016 Feb 24.
Dynamic Combinatorial Chemistry (DCC) has proven to be a reliable method for identifying hit compounds for target nucleic acid (DNA and RNA) sequences. Typically, these hit compounds are subjected to a lengthy process of optimization via traditional medicinal chemistry. Here, we examine the potential of DCC to also generate and test variations on a hit compound as a method for probing the binding site of an RNA-targeted compound. Specifically, we demonstrate that addition of linker dithiols to a disulfide library containing a known binder to the HIV-1 frameshift-stimulatory RNA (a critical regulator of the HIV life cycle) can yield a mixture of new bridged structures incorporating the dithiol, depending on dithiol structure. Equilibration of this library with the HIV FSS RNA resulted in selection of the original disulfide in preference to bridged structures, suggesting incorporation of the bridge is not compatible with this particular binding site. Application of this strategy to other RNA targets should allow for rapidly profiling the affinity of modified compounds.
动态组合化学（DCC）已被证明是一种用于识别针对靶核酸（DNA和RNA）序列的先导化合物的可靠方法。通常，这些先导化合物要经过传统药物化学的漫长优化过程。在此，我们研究了DCC作为一种探测RNA靶向化合物结合位点的方法，生成并测试先导化合物变体的潜力。具体而言，我们证明，向包含一种已知可与HIV-1移码刺激RNA（HIV生命周期的关键调节因子）结合的二硫键文库中添加连接二硫醇，根据二硫醇的结构，可产生包含二硫醇的新的桥连结构混合物。该文库与HIV FSS RNA平衡后，优先选择了原始二硫键而非桥连结构，这表明桥连结构的引入与这个特定的结合位点不兼容。将该策略应用于其他RNA靶点，应能快速分析修饰化合物的亲和力。
