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（由应用提供）：核酸都是药物设计的途径，无论是作为治疗还是作为靶标的。在这里，我们建议建立新方法来识别抗生素核糖体靶标和铅化合物。靶向特定的RNA，例如与细菌的增殖和存活有关的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序列特异性的小分子，以进行新的抗核糖体活动。我们将构建可以有效地在细胞内传递的抗菌剂构序核糖体靶向寡聚物。核糖体成分之间的复合物将作为小分子药物库的靶标的探索，使核糖体失活，停止细菌蛋白质合成并导致细菌死亡。 Nubads独特的实验方法和技术将使我们能够靶向以前未探索的核糖体区域，以针对抗细菌剂的易感性。这项工作解决了一个重要的世界健康问题，抗菌素的抵抗力，并为解决这个问题的新颖解决方案提出了创造性的步骤。这里提出的工作是涵盖固相机合成，寡核苷酸递送，RNA靶向筛查和抗菌研究的多学科努力，描述了RRNA序列特异性细胞可渗透性粘合剂作为抗体疗法的序列特异性细胞的发展。拟议工作的成功将是当前可用的核糖体特异性方法的重要补充。我们建议使用一个小的rRNA靶序列来设计可以进行的结合物来抑制细菌的生长，从而开发了开发序列特异性RNA靶向治疗的可能性。