Mukherjee Herschel, Blain J Craig, Vandivier Lee E, Chin Donovan N, Friedman Jessica E, Liu Fei, Maillet Ashley, Fang Chao, Kaplan Jenifer B, Li Jinxing, Chenoweth David M, Christensen Allan Beck, Petersen Lars Kolster, Hansen Nils Jakob Vest, Barrera Luis, Kubica Neil, Kumaravel Gnanasambandam, Petter Jennifer C
Arrakis Therapeutics, 830 Winter Street, Waltham, Massachusetts, United States.
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania, United States.
ACS Chem Biol. 2020 Sep 18;15(9):2374-2381. doi: 10.1021/acschembio.0c00357. Epub 2020 Aug 17.
RNA is emerging as a valuable target for the development of novel therapeutic agents. The rational design of RNA-targeting small molecules, however, has been hampered by the relative lack of methods for the analysis of small molecule-RNA interactions. Here, we present our efforts to develop such a platform using photoaffinity labeling. This technique, termed hotoaffinity vluation of NA igation-uencing (PEARL-seq), enables the rapid identification of small molecule binding locations within their RNA targets and can provide information on ligand selectivity across multiple different RNAs. These data, when supplemented with small molecule SAR data and RNA probing data enable the construction of a computational model of the RNA-ligand structure, thereby enabling the rational design of novel RNA-targeted ligands.
RNA正成为新型治疗药物开发的一个有价值的靶点。然而，由于相对缺乏分析小分子与RNA相互作用的方法，靶向RNA的小分子的合理设计受到了阻碍。在此，我们展示了我们利用光亲和标记开发这样一个平台的努力。这项技术，称为核酸连接测序的光亲和评估（PEARL-seq），能够快速识别小分子在其RNA靶点内的结合位置，并能提供关于配体对多种不同RNA的选择性的信息。这些数据，当与小分子构效关系数据和RNA探测数据相结合时，能够构建RNA-配体结构的计算模型，从而实现新型RNA靶向配体的合理设计。
