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Thio-Ether Nucleic Acids: Clicking Together Synthetic Poly(Nucleic Acids)

硫醚核酸：点击在一起合成聚（核酸）

基本信息

批准号：
8440227
负责人：
Christopher N Bowman
金额：
$ 17.92万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8440227
关键词：
Acrylates Adenine Amino Acids Base Pair Mismatch Base Pairing Base Sequence Behavior Binding Biological Biological Assay Biological Process Characteristics Chemicals Chemistry Codon Nucleotides Complementary DNA Cytosine DNA DNA Binding DNA Sequence Detection Devices Diagnosis Disease Drug Delivery Systems Enzymes Ethers Forms Controls Gene Mutation Genetic Genetic Markers Genetic Materials Genetic Transcription Genomics Guanine In Vitro KRAS2 gene Lead Malignant Neoplasms Mediating Molecular Structure Molecular Weight Mutation Nanostructures Nature Nucleic Acid Hybridization Nucleic Acids Nucleic acid sequencing Oligonucleotides Oncogenes Peptide Nucleic Acids Peptide Synthesis Phase Production RNA Reaction Research Resistance Science Single Nucleotide Polymorphism Solid Solutions Specificity Structure Sulfhydryl Compounds Temperature Thymine Translations Treatment outcome Vertebral column Work aptamer base biological systems cancer diagnosis cost design disease diagnosis drug development in vivo knockout gene monomer nanoscale nanostructured novel nucleic acid structure public health relevance synthetic peptide

项目摘要

DESCRIPTION (provided by applicant): DNA represents one of the most capable and powerful biomolecular structures: functional as genetic material, hybridizing to complementary strands, being functional as aptamers, and active in transcription and translation as well as being capable of inducing organization and enabling the formation of designed nanostructures. DNA performs numerous natural biological functions as well as being used in drug development, biodetection, gene knockout, and genomics assays as well as many others. Despite these capabilities, DNA remains prohibitively expensive and/or difficult to implement for use in any but the most valuable applications, particularly in the materials realm. The overall hypothesis of the proposed research is that the synergistic combination of thiol-ene-based click chemistry with oligonucleotide synthesis will lead to the formation of an entirely new and highly capable class of oligonucleotide structures, i.e., thio-ether nucleic acids (TNAs), that are capable of interacting with sequence specificity with DNA in vivo, in vitro and in biofunctional applications such as biodetection and as aptamer mimics. The synergistic combination of thiol-ene click chemistry with synthetic oligonucleotide production will yield functional oligonucleotides that have enhanced DNA-binding capability, are easier to produce at scale, and have distinct chemical advantages over DNA and PNA structures. Broadly, the overall aim of this project is to develop and perform preliminary characterization of an entirely new class of oligonucleotide molecules that would have significant advantages over both biological oligonucleotides (DNA and RNA) as well as the synthetic PNAs for DNA hybridization, for biodetection, and for other biofunctional applications. The specific aims of this work are to (i) synthesize base-functionalized TNA monomers, (ii) form controlled sequence oligomers from these monomers and evaluate their capacity for strong, selective hybridization with DNA, and (iii) demonstrate the utility of these TNA sequences in SNP detection of the KRAS oncogene.

描述（由申请人提供）：DNA代表了最有能力和最强大的生物分子结构之一：具有遗传物质的功能，与互补链杂交，具有适体的功能，在转录和翻译中具有活性，并且能够诱导组织并能够形成设计的纳米结构。 DNA 具有多种天然生物学功能，并可用于药物开发、生物检测、基因敲除和基因组学分析以及许多其他领域。尽管有这些能力，DNA 仍然非常昂贵和/或难以用于除最有价值的应用之外的任何应用，特别是在材料领域。拟议研究的总体假设是，基于硫醇烯的点击化学与寡核苷酸合成的协同组合将导致形成一种全新的、高性能的寡核苷酸结构，即硫醚核酸（TNA），它能够在体内、体外和生物功能应用中与 DNA 进行序列特异性相互作用，例如生物检测和适体模拟。硫醇-烯点击化学与合成寡核苷酸生产的协同组合将产生功能性寡核苷酸，其具有增强的 DNA 结合能力，更容易大规模生产，并且比 DNA 和 PNA 结构具有明显的化学优势。总体而言，该项目的总体目标是开发并初步表征一类全新的寡核苷酸分子，该分子相对于生物寡核苷酸（DNA 和 RNA）以及用于 DNA 杂交、生物检测和其他生物功能应用的合成 PNA 具有显着优势。这项工作的具体目标是 (i) 合成碱基功能化的 TNA 单体，(ii) 从这些单体形成受控序列寡聚物，并评估它们与 DNA 强选择性杂交的能力，以及 (iii) 证明这些 TNA 序列在 KRAS 癌基因的 SNP 检测中的实用性。