Screening the Ribosome for New Target Sites

筛选核糖体的新靶位点

• 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
• 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

 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，既作为治疗剂又作为靶标。在这里，我们建议建立新的方法来识别抗生素核糖体靶标和先导化合物。靶向参与细菌增殖和存活的特异性RNA（如rRNA）是一种有前途的方法。我们正在开发快速和低成本的方法来筛选新的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作为抗菌剂，可以有效地在细胞内递送。核糖体组分之间的复合物将被用作小分子药物库的靶标，这些药物库使核糖体停止，停止细菌蛋白质合成并导致细菌死亡。NUBAD独特的实验方法和技术将使我们能够靶向以前未探索过的对抗菌剂敏感的核糖体区域。这项工作解决了一个重要的世界卫生问题，抗菌素耐药性，并提出了创造性的步骤，以解决这一问题的新方法。 这里提出的工作，一个多学科的努力，包括固相有机合成，寡核苷酸递送，RNA靶向筛选和抗菌研究，描述了序列特异性的细胞渗透性结合剂的rRNA抗菌治疗的发展。拟议工作的成功将是对目前可用的核糖体特异性抗菌治疗方法的重要补充。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，从而为开发序列特异性RNA靶向治疗剂开辟了可能性。