Robertson Andrew W, Sandoval Jorge, Mohamed Osama G, Zhuang Yihao, Gallagher Erin E, Schmidt Jennifer, Caratelli Lisa, Menon Arya, Schultz Pamela J, Torrez Rachel M, Hay Catherine L, Bell Bailey A, Price Paul A, Garner Amanda L, Tripathi Ashootosh
Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States.
Natural Products Discovery Core, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States.
ACS Med Chem Lett. 2021 Apr 2;12(6):878-886. doi: 10.1021/acsmedchemlett.1c00046. eCollection 2021 Jun 10.
MicroRNAs (miRNAs) are a family of small noncoding RNAs that regulate gene expression. Due to their important activity in the fine-tuning of protein translation, abnormal expression of miRNAs has been linked to many human diseases, making the targeting of miRNAs attractive as a novel therapeutic strategy. Accordingly, researchers have been heavily engaged in the discovery of small molecule modulators of miRNAs. With an interest in the identification of new chemical space for targeting miRNAs, we developed a high-throughput screening (HTS) technology, catalytic enzyme-linked click chemistry assay (cat-ELCCA), aimed at the discovery of small molecule ligands for pre-miR-21, a miRNA that is frequently overexpressed in human cancers. From our HTS campaign, we found that natural products, a source of many impactful human medicines, may be a promising source of potential pre-miR-21-selective maturation inhibitors. Herein we describe our first efforts in natural product inhibitor discovery leading to the identification of a depsipeptide class of natural products as RNA-binding inhibitors of Dicer-mediated miRNA processing.
微小RNA（miRNA）是一类调控基因表达的小型非编码RNA。由于其在蛋白质翻译微调中的重要活性，miRNA的异常表达与许多人类疾病相关，这使得将miRNA作为一种新型治疗策略的靶点颇具吸引力。因此，研究人员一直致力于发现miRNA的小分子调节剂。出于对寻找靶向miRNA新化学空间的兴趣，我们开发了一种高通量筛选（HTS）技术，即催化酶联点击化学分析（cat-ELCCA），旨在发现针对pre-miR-21的小分子配体，pre-miR-21是一种在人类癌症中经常过度表达的miRNA。通过我们的高通量筛选活动，我们发现天然产物，这一许多有影响力的人类药物的来源，可能是潜在的pre-miR-21选择性成熟抑制剂的一个有前景的来源。在此，我们描述了我们在天然产物抑制剂发现方面的首次努力，最终鉴定出一类环肽类天然产物作为Dicer介导的miRNA加工的RNA结合抑制剂。
