A novel assay for RNA targeted drugs

描述（由申请人提供）：NUBAD，LLC是一家致力于鉴定靶向核酸的治疗剂的药物发现公司。该项目旨在合成和表征一类新型的荧光标记的氨基糖苷类，其在RNA结合时表现出显着的荧光变化。氨基糖苷类抗生素是一类有效的抗生素，通过与核糖体RNA上的保守位点结合来阻断细菌蛋白质合成。该项目的目的是开发一种基于荧光的A位点靶向药物筛选方法，用于快速筛选RNA结合抗菌药物。 公共卫生相关性：氨基糖苷类抗生素通过结合核糖体RNA上的保守位点阻断细菌蛋白质合成。这些抗生素是临床上重要的药物，可以对抗广谱细菌感染，但可能导致严重的副作用，如肾损伤和听力损失。抗生素耐药性的出现和与当前药物库相关的高水平毒性要求开发筛选具有高效力和低毒性的期望性质的新型抗生素的有效方法。NUBAD，LLC，彭德尔顿，SC与PI的实验室，克莱姆森大学，SC合作，最近确定了一种荧光新霉素缀合物，用于探测药物与RNA靶点的结合。该提案描述了一个I期项目，该项目将确定在创新筛选中使用荧光-新霉素探针的技术和科学可行性，该筛选适用于高通量筛选新的氨基糖苷类抗生素。该I期应用将开发用于高通量应用的探针，然后使用靶向筛选来检查测定稳健性。然后检查选定化合物的抗菌活性和作用机制。

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.