Preclinical Development of Lead Compounds Targeting Myotonic Dystrophy

描述（由申请人提供）：（CUG）重复RNA对MBNL1的隔离被认为是1型肌强直性营养不良（DM1）的关键分子相互作用。因此，能够抑制这种相互作用的新化合物构成了开发有效治疗剂的重要潜在线索。我们最近描述了一组能够以显著的选择性结合（CUG）重复RNA并抑制MBNL1结合的化合物的发现。我们提出的研究以三个目标为中心，这些目标将扩展这一重要的初步结果，并获得适合临床开发的化合物。首先，我们将确定能够维持选择性（CUG）重复RNA结合的最小结合肽，并将探索肽n -甲基化对亲和力的影响。其次，我们将在基于置换的高通量筛选中使用最高亲和力的先导化合物来筛选新的（CUG）重复结合化学型。最后，我们将进行一系列细胞试验，以确定新化合物在细胞环境中抑制（CUG） RNA - MBNL1结合的能力。

DESCRIPTION (provided by applicant): Sequestration of MBNL1 by (CUG) repeat RNA is believed to be a key molecular interaction in type 1 myotonic dystrophy (DM1). Thus, new compounds able to inhibit this interaction constitute important potential leads towards the development of effective therapeutic agents. We recently described the discovery of a set of compounds able to bind (CUG) repeat RNA with significant selectivity and inhibit MBNL1 binding. Our proposed research centers on three Aims that will expand on this important initial result, and obtain compounds suitable for clinical development. First, we will determine the minimum binding peptide capable of maintaining selective (CUG) repeat RNA binding, and will explore the effect of peptide N-methylation on affinity. Second, we will employ the highest-affinity lead compound in a displacement-based high throughput screen for new (CUG) repeat-binding chemotypes. Finally, we will carry out a series of cellular assays to determine the ability of new compounds to inhibit (CUG) RNA - MBNL1 binding in a cellular context. PUBLIC HEALTH RELEVANCE: Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, affecting 1 in 8000 people. The disease is believed to result from the accumulation of a toxic RNA, termed a "CUG repeat", which sequesters a protein critical for proper cellular function. Building on a discovery made in our laboratory of a molecule able to bind CUG repeat RNA, we will carry out a series of experiments designed to yield a new molecule with higher activity and improved drug-like properties. The overall goal of the project will be to obtain at least one compound suitable for development as a therapeutic agent.