A novel assay for RNA targeted drugs

描述(申请人提供)：NUBAD，LLC是一家致力于识别针对核酸的治疗剂的药物发现公司。本项目旨在合成和表征一类新型的荧光标记氨基糖苷类化合物，它们在与RNA结合时表现出显著的荧光变化。氨基糖苷类抗生素是一类有效的抗生素，通过与核糖体RNA上的保守位置结合来阻止细菌蛋白质的合成。该项目的目的是开发一种创新的基于荧光的A位靶向药物筛选方法，用于快速筛选RNA结合的抗菌药。 公共卫生相关性：氨基糖苷类抗生素通过结合核糖体RNA上的保守位置来阻止细菌蛋白质的合成。这些抗生素是临床上重要的制剂，可以对抗广泛的细菌感染，但会引起严重的副作用，如肾脏损伤和听力损失。抗生素耐药性的出现和与当前药物武器库相关的高水平毒性要求开发高效的方法来筛选具有高效力和低毒性的新型抗生素。NUBAD，LLC，Pendleton，SC与Pi的实验室，南卡罗来纳州克莱姆森大学合作，最近发现了一种用于探测药物与RNA靶标结合的荧光新霉素结合物。该提案描述了一个第一阶段项目，该项目将确定在一种适用于新氨基糖苷类抗生素高通量筛查的创新筛查中使用荧光-新霉素探针的技术和科学可行性。这个第一阶段的应用程序将开发用于高通量应用程序的探针，然后使用目标屏幕来检查分析的稳健性。然后将检查选定的化合物的抗菌活性和作用机理。

DESCRIPTION (provided by applicant): NUBAD, LLC is a drug discovery company devoted to identifying therapeutic agents that target nucleic acids. This project is designed to synthesize and characterize a novel class of fluorescently-labeled aminoglycosides that exhibit a dramatic change in fluorescence upon RNA binding. Aminoglycosides are a potent class of antibiotics that block bacterial protein synthesis by binding to a conserved site on ribosomal RNA. It is the purpose of the project to develop an innovative fluorescence-based screen for A-site targeted drugs for rapid screening of RNA binding antibacterials. PUBLIC HEALTH RELEVANCE: The aminoglycoside class of antibiotics block bacterial protein synthesis by binding a conserved site on ribosomal RNA. These antibiotics are clinically important agents that combat a broad spectrum of bacterial infections but can cause serious side effects such as kidney damage and hearing loss. The emergence of antibiotic resistance and high level of toxicity associated with the current arsenal of drugs demands the development of efficient methods of screening for novel antibiotics with the desirable properties of high potency and low toxicity. NUBAD, LLC, Pendleton, SC in collaboration with PI's lab, Clemson University, SC, has recently identified a fluorescent neomycin conjugate that is being used to probe drug binding to RNA targets. This proposal describes a phase I project that will determine the technical and scientific feasibility of using a fluorescent-neomycin probe in an innovative screen suitable for a high-throughput screen for new aminoglycoside based antibiotics. This phase I application will develop the probe for high throughput applications and then use the targeted screen to check for assay robustness. Selected compounds will then be checked for antibacterial activity and mechanism of action.