Delivery of chemically modified PNA oligomers

化学修饰的 PNA 寡聚物的递送

基本信息

批准号：
10006671
负责人：
DEV PRIYA ARYA
金额：
$ 30万
依托单位：
NUBAD, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-06 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006671
关键词：
Address Amides Amino Sugars Aminoglycosides Animal Disease Models Anti-Bacterial Agents Antibiotic Resistance Antibiotics Awareness Bacteria Base Pairing Binding Biological Assay Biological Availability Books Boston Cells Chemicals Clinic Communicable Diseases Complement Complex Congresses Consultations Coupled Data Development Disease Drug Design Drug Targeting Drug resistance Elements Escherichia coli Face Gram-Negative Bacteria Growth Health High Pressure Liquid Chromatography Human Hybrids In Vitro Infection Institute of Medicine (U.S.)Legal patent Letters Libraries Link Lipids Locales Membrane Methods Modernization Mus Nucleic Acid Binding Nucleic Acids Oligonucleotides Organic Synthesis Pathogenicity Permeability Pharmaceutical Preparations Pharmacologic Substance Phase Predisposition Prevention Protein Synthesis Inhibitors RNA RNA Binding RNA Sequences Reporting Ribosomal RNA Ribosomes Site Solid Specificity Structure Surgeon Tail Technology Therapeutic Time Tissues Toxic effect Translating United States United States National Academy of Sciences United States National Institutes of Health Work antibiotic resistant infections antimicrobial antimicrobial drug base comparative cost design dosage drug development efficacy study human disease in vivo microbial multidisciplinary new technology novel nucleic acid delivery pathogen prevent screening small molecule success targeted treatment uptake web site

项目摘要

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.

项目概要 RNA 是药物设计的经过验证的靶点，无论是作为治疗还是作为靶点。靶向特定RNA，例如参与增殖和存活的rRNA 细菌是一种有前途的方法。我们正在开发快速且低成本的方法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化学修饰核糖体靶向寡聚体被有效地传递到细胞内，解决了关键目标 PAR-17-036（产生用于输送核酸的新技术和产品将酸进入细胞和组织以治疗或预防人类疾病）。将利用核糖体成分之间的复合物作为使核糖体失活的小分子药物库的靶标。 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对微生物敏感性的核糖体区域目标。这里提出的工作是一项多学科的努力，涵盖固相有机合成、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的发展 rRNA 的渗透性结合剂。拟议工作的成功将具有重大意义除了目前药物开发中可用的核糖体特异性方法之外。我们建议使用小的 rRNA 靶序列来设计可以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。