A novel assay for RNA targeted drugs

RNA靶向药物的新型检测方法

基本信息

批准号：
8203072
负责人：
DEV PRIYA ARYA
金额：
$ 28.55万
依托单位：
NUBAD, LLC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8203072
关键词：
Abbreviations Adverse effects Affect Affinity Alkynes Amino Sugars Aminoglycoside Antibiotics Aminoglycosides Anti-Bacterial Agents Antibiotic Resistance Antibiotics Azides Bacteria Bacterial Infections Bacterial Proteins Binding Biological Assay Books Cell Nucleus Cells Chemistry Collaborations Communicable Diseases Congresses Development Disease Drug Delivery Systems Enzymes Ethidium Exhibits Fluorescein Fluorescence Growth Hexoses In Vitro Kanamycin Kidney Label Laboratories Laser Scanning Confocal Microscopy Left Libraries Link Methods Minimum Inhibitory Concentration measurement Modeling Monitor Nature Neomycin Nucleic Acids Oligonucleotides Pharmaceutical Preparations Phase Property Protein Biosynthesis Pseudomonas aeruginosa RNA RNA Binding RNA, Ribosomal, 16S Ribosomal RNA Ribosomes Scheme Screening procedure Site Specificity Staphylococcus aureus Surgeon Testing Therapeutic Agents Thiourea Time Toxic effect Translations Triazoles United States Universities Virulent antimicrobial bactericide base combat design drug discovery hearing impairment high throughput screening improved innovation killings microbial mutant novel resistance mechanism small molecule

项目摘要

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.

描述（由申请人提供）：NUBAD, LLC 是一家药物发现公司，致力于识别靶向核酸的治疗剂。该项目旨在合成和表征一类新型荧光标记氨基糖苷类药物，这些氨基糖苷类药物在与 RNA 结合后会表现出巨大的荧光变化。氨基糖苷类是一类强效抗生素，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 结合抗菌药物。公众健康相关性：氨基糖苷类抗生素通过结合核糖体 RNA 上的保守位点来阻断细菌蛋白质合成。这些抗生素是临床上重要的药物，可以对抗广泛的细菌感染，但可能会导致严重的副作用，例如肾脏损伤和听力损失。与当前药物库相关的抗生素耐药性和高毒性的出现要求开发有效的方法来筛选具有高效低毒特性的新型抗生素。南卡罗来纳州彭德尔顿的 NUBAD, LLC 与南卡罗来纳州克莱姆森大学的 PI 实验室合作，最近发现了一种荧光新霉素缀合物，可用于探测药物与 RNA 靶标的结合。该提案描述了一个第一阶段项目，该项目将确定在适合高通量筛选新型氨基糖苷类抗生素的创新筛选中使用荧光新霉素探针的技术和科学可行性。这一阶段的应用将开发用于高通量应用的探针，然后使用目标筛选来检查测定的稳健性。然后将检查所选化合物的抗菌活性和作用机制。