Development of Peptide Antibiotic Nucleic Acids

肽类抗生素核酸的开发

• 批准号: 8780584
• 负责人: DEV PRIYA ARYA
• 金额: $ 29.58万
• 依托单位: NUBAD, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-20 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780584
• 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; Cell physiology; Cells; Cessation of life; Communicable Diseases; Complement; Complex; Congresses; Development; Disease; Drug Design; Drug Targeting; Drug resistance; Enzymes; Epidemic; Escherichia coli; Generations; Growth; Head; Health Care Costs; High Pressure Liquid Chromatography; Human; Hybrids; In Vitro; Infection; Institute of Medicine (U.S.); Knowledge; Lead; Libraries; Link; Locales; Malaria; Marketing; Methods; Neomycin; Nosocomial Infections; Nucleic Acids; Organic Synthesis; Parasites; Peptide Antibiotics; Peptide Nucleic Acids; Pharmaceutical Preparations; Phase; Predisposition; Preparation; Protein Biosynthesis; RNA Binding; RNA Interference; Reporting; Research; Resistance; Ribosomal RNA; Ribosomes; Site; Solid; Solutions; Specificity; Staphylococcal Infections; Structure; Surgeon; Tail; Technology; Testing; Therapeutic; Thiourea; Time; Toxic effect; Translations; Tuberculosis; United States; United States National Academy of Sciences; Universities; Validation; Virus; Work; World Health; antimicrobial; antimicrobial drug; bacterial resistance; combat; comparative; cost; design; fighting; innovation; microorganism; multidisciplinary; novel; novel therapeutics; public health relevance; scale up; screening; small molecule; success; therapeutic target; uptake; web site

DESCRIPTION (provided by applicant): One of the challenges of research in infectious diseases is to find ways to use the increasing knowledge of the mechanisms underlying disease transformation and progression to develop novel therapeutic strategies for diseases such as increasing menace of bacterial infections. Targeting specific RNA, such as rRNA which are involved in proliferation and survival of bacteria is a promising approach. The world is rapidly heading towards a pre-1940's scenario when it comes to fighting infectious disease. Antimicrobial resistance is a growing problem on a global scale, greatly hampering our abilities to quell worldwide epidemics such as tuberculosis and malaria, as well as the simple staphylococcus infection. Unless innovative strategies are developed to produce robust and effective new classes of antibiotics, health care costs will continue to climb and we will completely lose our ability to combat even the most common infection. 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. 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. 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, 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）：传染病研究的挑战之一是找到方法，利用对疾病转化和进展机制的不断增长的了解来开发针对诸如日益增加的细菌感染威胁等疾病的新治疗策略。靶向特定的RNA，例如参与细菌增殖和存活的rRNA，是一种很有前景的方法。在抗击传染病方面，世界正迅速走向 1940 年代之前的局面。抗生素耐药性是全球范围内日益严重的问题，极大地阻碍了我们平息全球流行病（例如结核病和疟疾以及简单的葡萄球菌感染）的能力。除非开发出创新策略来生产强健有效的新型抗生素，否则医疗保健成本将继续攀升，我们将完全失去对抗最常见感染的能力。 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。在这里，我们建议建立鉴定抗生素核糖体靶点和先导化合物的新方法。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物作为抗菌剂。核糖体成分之间的复合物将被用作小分子药物库的靶标，这些药物库使核糖体失活，阻止细菌蛋白质合成并引起细菌感染。 死亡。 NUBAD 独特的实验方法和技术将使我们能够瞄准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健康问题——抗菌素耐药性，并提出了创造性的步骤，以寻求解决该问题的新方法。 这里提出的工作是一项多学科工作，涵盖固相有机合成、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。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大补充。我们建议使用小的 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 靶向疗法提供了可能性。