Department of Chemistry and Chemical Biology , University of New Mexico , 300 Terrace Street NE , Albuquerque , New Mexico 87131 , United States.
Department of Chemistry , University of South Florida , 4202 E. Fowler Avenue , Tampa , Florida 33620 , United States.
Mol Pharm. 2019 Feb 4;16(2):914-920. doi: 10.1021/acs.molpharmaceut.8b01247. Epub 2019 Jan 15.
miR-155 plays key promoting roles in several cancers and emerges as an important anticancer therapeutic target. However, the discovery of small molecules that target RNAs is challenging. Peptidomimetics have been shown to be a rich source for discovering novel ligands to regulate cellular proteins. However, the potential of using peptidomimetics for RNA targeting is relatively unexplored. To this end, we designed and synthesized members of a novel 320 000 compound macrocyclic peptidomimetic library. An affinity-based screening protocol led to the identification of a pre-miR-155 binder that inhibits oncogenic miR-155 maturation in vitro and in cell and induces cancer cell apoptosis. The results of this investigation demonstrate that macrocyclic peptidomimetics could serve as a new scaffold for RNA targeting.
miR-155 在几种癌症中发挥关键促进作用，是一种重要的抗癌治疗靶点。然而，发现靶向 RNA 的小分子具有挑战性。肽模拟物已被证明是发现调节细胞蛋白的新型配体的丰富来源。然而，使用肽模拟物靶向 RNA 的潜力相对尚未得到探索。为此，我们设计并合成了一种新型的 320000 种化合物大环肽模拟物文库的成员。基于亲和力的筛选方案导致鉴定出一种前 miR-155 结合物，该结合物可抑制体外、细胞内和诱导癌细胞凋亡的致癌 miR-155 成熟。这项研究的结果表明，大环肽模拟物可以作为 RNA 靶向的新支架。
