Delivery of chemically modified PNA oligomers

项目摘要 RNA是药物设计的有效靶点，无论是作为治疗药物还是作为靶点。 靶向特定的RNA，如参与细胞增殖和存活的rRNA， 细菌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， 筛选新的抗核糖体活性的序列特异性小分子。我们将 构建序列特异性化学修饰的核糖体靶向寡聚体， 在细胞内有效传递，解决以下关键目标： PAR-17-036（产生用于递送核酸的新技术和产品） 酸进入细胞和组织，以治疗或预防 人类疾病）。核糖体成分之间的复合物将被利用 作为包裹核糖体的小分子药物文库的靶点。 NUBAD独特的实验方法和技术将使我们能够瞄准 核糖体区域以前没有探索过对微生物的敏感性 目标的 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，抗菌 活性和体内功效研究描述了序列特异性细胞 rRNA的渗透性结合物。拟议工作的成功将是一个重大的 除了目前可用的核糖体特异性药物开发方法。我们 建议使用小rRNA靶序列来设计可以被 用于抑制微生物生长，为开发序列提供了可能性- 特异性RNA靶向治疗。

PROJECT SUMMARY RNA is a validated target for drug design, both as therapeutic and as a target. 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 chemically modified ribosomal targeting oligomers that can be effectively delivered inside the cell, addressing the key objective of PAR-17-036 (to generate new technologies and products for delivering nucleic acids into cells and tissues for the purpose of treatment or prevention of human disease). Complexes between ribosomal components will be exploited as targets for small molecule drug libraries that-inactivate the ribosome. NUBADs unique experimental approaches and technologies will allow us to target ribosomal regions not previously explored for susceptibility against microbial targets. The work proposed here, a multidisciplinary effort encompassing solid-phase organic synthesis, oligonucleotide delivery, RNA targeted screening, antimicrobial activity, and in vivo efficacy studies describes the development of sequence-specific cell permeable binders of rRNA. The success of the proposed work would be a significant addition to currently available ribosome-specific approaches in drug development. We propose using a small rRNA target sequences to design conjugates that can be employed to inhibit microbial growth, opening possibilities for developing sequence- specific RNA targeted therapeutics.