A Rapid Assay for RNA Targeted Drugs

RNA 靶向药物的快速检测

基本信息

批准号：
8884616
负责人：
DEV PRIYA ARYA
金额：
$ 66.37万
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 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884616
关键词：
Accounting Address Affinity Amikacin Amino Sugars Aminoglycosides Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Antineoplastic Agents Antiviral Agents Bacteria Bacterial Infections Binding Biological Assay Cells Cessation of life Clinical Collaborations Derivation procedure Dermal Development Disease Drug Targeting Environment Equilibrium Escherichia coli Fibroblasts Fluorescein Fluorescence Growth HIV Health Hospitals Housing Human Immune response Industry Infection Kanamycin Length Libraries Life Liquid substance Malignant Neoplasms Medical Modeling Neomycin Nucleic Acids Pathology Pharmaceutical Preparations Phase Preparation RNA Reader Reporter Research Ribosomes Robot Sales Site Skin South Carolina Structure System Technology Tobramycin Toxic effect United States United States National Institutes of Health Universities Work antimicrobial bacterial resistance base clinically relevant commercialization cost cytotoxicity deprotonation drug discovery effective therapy functional group high throughput screening in vivo keratinocyte nephrotoxicity next generation novel ototoxicity pathogen resistant strain screening

Accounting Address Affinity Amikacin Amino Sugars Aminoglycosides Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Antineoplastic Agents Antiviral Agents Bacteria Bacterial Infections Binding Biological Assay Cells Cessation of life Clinical Collaborations Derivation procedure Dermal Development Disease Drug Targeting Environment Equilibrium Escherichia coli Fibroblasts Fluorescein Fluorescence Growth HIV Health Hospitals Housing Human Immune response Industry Infection Kanamycin Length Libraries Life Liquid substance Malignant Neoplasms Medical Modeling Neomycin Nucleic Acids Pathology Pharmaceutical Preparations Phase Preparation RNA Reader Reporter Research Ribosomes Robot Sales Site Skin South Carolina Structure System Technology Tobramycin Toxic effect United States United States National Institutes of Health Universities Work antimicrobial bacterial resistance base clinically relevant commercialization cost cytotoxicity deprotonation drug discovery effective therapy functional group high throughput screening in vivo keratinocyte nephrotoxicity next generation novel ototoxicity pathogen resistant strain screening

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项目摘要

DESCRIPTION (provided by applicant): Some of the most significant therapies that treat disease target nucleic acids. Drugs that target nucleic acid include cancer drugs, antibiotics, and antivirals. Combined these classes of drugs have annual sales worldwide of ~$139 billion. Antibiotics that target nucleic acids account for $14.5 billion of the $42 billion of sales annuall for all antibiotics, and account for three of the top five classes of antibiotics. The crisis of antibiotic resistance has resulted in a significant cost, both financially and in human life. Seveny percent of infectious bacteria are resistant to at least one commonly used antibiotic treatment (NIH). In the United States alone, 1.7 million people get an infection while in a hospital environment with just under 100,000 of these cases resulting in death (NIH). This situation demonstrates the increased need for the development of new antibiotic therapies. A rapid assay examining the binding affinity of novel aminoglycosides to the A-site and other nucleic acid sites will facilitate the discovery of effective therapies. In Phase I, we have developed a fluorescence based competition assay using a 27-base RNA model of the ribosomal A-site and a novel fluorescent reporter molecule, F-neo. This assay is readily adaptable to a high throughput format as larger compound libraries are established. In Phase II our specific aims are 1) develop an automated fluorescent based assay for screening broad based RNA targets. This aim includes expanding the current assay to a high throughput automated screen and adapting the assay to include other nucleic acid drug targets. 2) Expand the library of aminoglycoside conjugated molecules. Phase I resulting in a small in house compound library that was screened using the assay developed in Phase I. In Phase II the library will be greatly expanded by the conjugation of aminoglycosides with different classes of compounds using a variety of linker lengths and types. 3) Screening of NUBAD compounds to determine and characterize the activity. This in vivo assay will help establish a correlation between "hits" from the assay and activity in the cell. At the conclusion of this work, we will have established a commercially available assay for the high throughput screening of compounds that target nucleic acids. This technology will fill a niche in the high throughput screening industry, and result in more efficien development of compounds that treat disease related to nucleic acid therapies.

描述（由申请人提供）：一些治疗疾病靶核酸的最重要的疗法。靶向核酸的药物包括癌症药物，抗生素和抗病毒药。这些类别的毒品在全球范围内的年销售额约为1390亿美元。靶向核酸的抗生素占所有抗生素的420亿美元销售中的145亿美元，占抗生素前五类抗生素中的三种。抗生素抗性危机在财务上和人类生活中都产生了巨大的成本。 7岁的传染细菌中有7％对至少一种常用的抗生素治疗（NIH）具有抗性。仅在美国，在医院环境中，有170万人感染，其中不到100,000例导致死亡（NIH）。这种情况表明，对新抗生素疗法的开发需求不断增加。一种快速检验新型氨基糖苷与A位点和其他核酸位点的结合亲和力的快速测定将有助于发现有效的疗法。在第一阶段，我们使用核糖体A位点的27碱基RNA模型和新型的荧光记者分子F-NEO开发了基于荧光的竞争测定法。由于建立了较大的复合库，因此很容易适应高通量格式。在第二阶段，我们的具体目的是1）开发一种基于荧光的自动化测定法，以筛选基于广泛的RNA靶标。该目的包括将当前测定法扩展到高吞吐量自动筛选，并适应包括其他核酸药物靶标。 2）扩大氨基糖苷共轭分子的文库。第一阶段导致了使用I阶段中开发的测定法进行筛选的小型内部化合物库。在第二阶段中，库将通过使用各种链接器长度和类型的不同类别的化合物的氨基糖苷与不同类别的化合物的结合来大大扩展库。 3）筛选nubad化合物以确定和表征活性。该体内测定将有助于建立来自细胞中测定的“命中”与活动之间的相关性。在这项工作结束时，我们将建立一个商业上可用的测定法，用于对靶向核酸的化合物的高吞吐量筛选。这项技术将填补高吞吐量筛查行业的利基市场，并导致更有效地发展与核酸疗法相关的疾病的化合物。