Screening the Ribosome for New Target Sites

 描述(申请人提供)：核酸是药物设计的途径，既是治疗方法，也是靶点。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。靶向特定的RNA，如与细菌的增殖和生存有关的rRNA是一种很有前途的方法。我们正在开发快速和低成本的方法来筛选序列特异性小分子的新的抗核糖体活性。我们将构建针对寡聚体的序列特异性核糖体作为抗菌药物，可以有效地在细胞内递送。核糖体成分之间的复合体将被用作小分子药库的靶标，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。NUBADs独特的实验方法和技术将使我们能够瞄准以前没有探索过的抗菌剂敏感性的核糖体区域。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，以期为这一问题找到新的解决方案。这里提出的工作是一项多学科的努力，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rRNA序列特异性细胞渗透结合物作为抗菌治疗药物的开发。这项拟议工作的成功将是对目前抗菌治疗中可用的核糖体特异性方法的重大补充。我们建议使用一个小的rRNA靶序列来设计可用于抑制细菌生长的结合物，为开发序列特异的RNA靶向疗法打开了可能性。

 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.