François-Moutal Liberty, Miranda Victor G, Mollasalehi Niloufar, Gokhale Vijay, Khanna May
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, United States.
Center of Innovation in Brain Science, Tucson, Arizona 85721, United States.
ACS Med Chem Lett. 2021 Apr 1;12(6):915-921. doi: 10.1021/acsmedchemlett.1c00060. eCollection 2021 Jun 10.
RNA targeting has gained traction over the past decade. It has become clear that dysregulation of RNA can be linked to many diseases, leading to a need for new scaffolds recognizing RNA specifically. Long noncoding RNAs are emerging as key controllers of gene expression and potential therapeutic targets. However, traditional targeting methods have overwhelmingly been focused on proteins. In this study, we used a protein computational tool and found several possible targetable pockets in a structurally characterized long noncoding RNA, MALAT1. Screening against those identified pockets revealed several hit compounds. We tested the binding of those compounds to MALAT1 RNA and tRNA as a negative control, using SPR. While several compounds were nonspecific binders, others were able to recognize MALAT1 specifically. One of them, MTC07, has an apparent affinity of 400.2 ± 14.4 μM. Although it has weak affinity, MTC07 is the first compound targeting MALAT1 originating from docking.
在过去十年中，RNA靶向受到了广泛关注。越来越明显的是，RNA失调与许多疾病有关，这就需要新的能够特异性识别RNA的支架。长链非编码RNA正成为基因表达的关键调控因子和潜在的治疗靶点。然而，传统的靶向方法主要集中在蛋白质上。在本研究中，我们使用了一种蛋白质计算工具，并在结构已明确的长链非编码RNA——MALAT1中发现了几个可能的可靶向口袋。针对这些已识别口袋进行筛选，发现了几种有活性的化合物。我们使用表面等离子体共振技术（SPR）测试了这些化合物与MALAT1 RNA的结合情况，并以tRNA作为阴性对照。虽然有几种化合物是非特异性结合剂，但其他一些化合物能够特异性识别MALAT1。其中一种化合物MTC07，其表观亲和力为400.2±14.4μM。尽管其亲和力较弱，但MTC07是首个通过对接产生的靶向MALAT1的化合物。
