Screening the Ribosome for New Target Sites

筛选核糖体的新靶位点

基本信息

批准号：
9140721
负责人：
DEV PRIYA ARYA
金额：
$ 32.5万
依托单位：
NUBAD, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-13 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9140721
关键词：
Address Amino Sugars Aminoglycosides Animals Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antimicrobial Resistance Awareness Bacteria Bacterial Infections Bacterial Proteins Base Pairing Binding Biological Assay Books Boston Bypass Cell Line Cells Cessation of life Communicable Diseases Complement Complex Congresses Development Drug Design Drug resistance Enzymes Escherichia coli Generations Growth High Pressure Liquid Chromatography Human Hybrids In Vitro Infection Institute of Medicine (U.S.)Lead Libraries Link Locales Marketing Methods Neomycin Nosocomial Infections Nucleic Acids Oligonucleotides Organic Synthesis Pharmaceutical Preparations Phase Predisposition Protein Biosynthesis Protein Synthesis Inhibitors RNA Binding Reporting Resistance Ribosomal RNA Ribosomes Site Solid Specificity Structure Surgeon Tail Technology Testing Therapeutic Thiourea Time Toxic effect Translations United States United States National Academy of Sciences Universities Work World Health antimicrobial antimicrobial drug bacterial resistance combat comparative cost design multidisciplinary novel pathogen phosphorodiamidate morpholino oligomer public health relevance response screening small molecule success targeted treatment uptake web site

项目摘要

DESCRIPTION (provided by applicant): Nucleic acids are avenues for drug design, both as therapeutics and as targets. Here we propose to establish new methods for identifying antibiotic ribosome targets and lead compounds. Targeting specific RNA, such as rRNA which are involved in proliferation and survival of bacteria is a promising approach. We are developing fast and low cost methods to screen sequence-specific small molecules for novel anti- ribosomal activities. We will construct sequence-specific ribosomal targeting oligomers as antibacterials, that can be effectively delivered inside the cell. Complexes between ribosomal components will be exploited as targets for small molecule drug libraries that- inactivate the ribosome, stopping bacterial protein synthesis and causing bacterial death. NUBADs unique experimental approaches and technologies will allow us to target ribosomal regions not previously explored for susceptibility against anti-bacterial agents. This work addresses an important world health issue, antimicrobial resistance, and presents creative steps towards a novel solution to this problem. The work proposed here, a multidisciplinary effort encompassing solid-phase organic synthesis, oligonucleotide delivery, RNA targeted screening and antibacterial studies, describes the development of sequence-specific cell permeable binders of rRNA as antibacterial therapeutics. The success of the proposed work would be a significant addition to currently available ribosome-specific approaches in antibacterial therapy. We propose using a small rRNA target sequences to design conjugates that can be employed to inhibit bacterial growth, opening possibilities for developing sequence-specific RNA targeted therapeutics.

描述（由申请人提供）：核酸是药物设计的途径，既可以作为治疗药物，也可以作为靶标。在此，我们建议建立新的方法来识别抗生素核糖体靶点和先导化合物，例如参与增殖的 rRNA。我们正在开发快速且低成本的方法来筛选具有新型抗核糖体活性的序列特异性小分子，我们将构建序列特异性核糖体靶向寡聚体。核糖体成分之间的复合物将被用作小分子药物库的靶标，这些药物可以使核糖体失活，阻止细菌蛋白质合成并导致细菌死亡。这项工作解决了一个重要的世界健康问题——抗菌素耐药性，并提出了针对该问题的新解决方案的创造性步骤。这里提出的工作是一项多学科工作，涵盖固相有机合成、寡核苷酸递送、RNA靶向筛选和抗菌研究，描述了rRNA序列特异性细胞渗透性结合剂作为抗菌疗法的开发。我们建议使用小 rRNA 靶序列来设计可用于抑制细菌生长的缀合物，为开发序列特异性 RNA 靶向方法提供了可能性。疗法。