Targeting Nucleic Acid Junctions with Small Molecules

摘要： 尽管现代医学和药物发现取得了重大进展，但仍然存在巨大的未满足的医疗需求。 需要对抗人类疾病。传染病和神经退行性疾病导致全球 严重的健康和经济问题。传统的药物发现工作集中在蛋白质 抑制剂现在正被更多的非传统方法所补充，如靶向蛋白质-蛋白质 相互作用，一度被认为是不可抵抗的目标。RNA和RNA-蛋白质相互作用进一步代表了 具有重大潜力的非传统药物靶点的例子。这主要是因为， RNA参与多种生物学过程，包括信息传递（mRNA）和基因调控 （siRNA和microRNA）到催化（核酶和核糖开关）。siRNA通路和多种 非编码RNA的世界具有调节功能，范围从细胞分化和染色体 组织对基因表达的调控。靶向RNA依赖过程的能力代表了 人类医学前沿的一个重要挑战。虽然不常被认为是药物的靶点， 发现，RNA靶向在抗生素如氨基糖苷类的情况下非常成功， 四环素类和大环内酯类抗生素。尽管取得了这些成功，但我们合理设计分子的能力， 以高亲和力和特异性靶向一些最重要的RNA结构基序， 存在的该提案旨在开发结构特异性核酸调节剂，用于靶向未满足的医疗需求。 需求我们将应用我们新开发的核酸调节剂靶向E. 大肠杆菌，一种对人类健康和NIH具有极大兴趣的病原体和模式生物。

Summary: Despite significant advances in modern medicine and drug discovery there are still tremendous unmet medical needs for combating human disease. Infectious diseases and neurodegenerative diseases contribute to global health and economic problems of significant magnitude. Traditional drug discovery efforts focused on protein inhibitors are now being complemented by more non-traditional approaches such as targeting protein-protein interactions, once considered undruggable targets. RNA and RNA-protein interactions represent further examples of non-traditional drug targets with significant potential. This is primarily due to the central role of RNA in a diverse array of biological processes ranging from information transfer (mRNA) and gene regulation (siRNA's and microRNA's) to catalysis (ribozymes and riboswitches). The siRNA pathway and the diverse world of non-coding RNA's have regulatory functions ranging from cellular differentiation and chromosomal organization to the regulation of gene expression. The ability to target RNA-dependent processes represents an important challenge at the frontier of human medicine. Although not often thought of as a target for drug discovery, RNA targeting has been very successful in the case of antibiotics such as the aminoglycosides, tetracyclines, and macrolide antibiotics. Despite these successes, our ability to rationally design molecules to target some of the most important RNA structural motifs with high affinity and specificity is essentially non- existent. This proposal aims to develop structure specific nucleic acid modulators for targeting unmet medical needs. We will apply our newly developed nucleic acid modulators to target RNA dependent processes in E. coli, a pathogen and model organism of great interest to human health and the NIH.