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，致力于鉴定靶向核酸的治疗剂。该项目旨在合成和表征一类新型的荧光标记的氨基糖苷，在RNA结合时表现出荧光发生巨大变化。氨基糖苷是一种有效的抗生素类，可通过结合核糖体RNA上的保守位点来阻断细菌蛋白的合成。该项目的目的是开发一种创新的基于荧光的筛选，以快速筛选RNA结合抗细菌的靶向药物。公共卫生相关性：通过在核糖体RNA上结合保守的位点，抗生素的氨基糖苷类阻断细菌蛋白的合成。这些抗生素是临床上重要的药物，可抵抗广泛的细菌感染，但会引起严重的副作用，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需要开发有效的新型抗生素筛查方法，具有高效力和低毒性的理想特性。 Nubad，LLC，Pendleton，SC与PI的实验室，Clemson University，SC合作，最近确定了一种荧光新霉素结合物，用于探测与RNA靶标探测药物结合的。该提案描述了一个I期项目，该项目将确定在适用于新的基于氨基糖苷的抗生素的高通量屏幕的创新屏幕中使用荧光 - 热霉素探针的技术和科学可行性。此阶段I应用程序将开发针对高通量应用程序的探针，然后使用目标屏幕检查测定鲁棒性。然后，将检查选定的化合物的抗菌活性和作用机理。