TEMPLATE DIRECTED COVALENT CROSS LINKING OF DNA

DNA 模板定向共价交联

• 批准号: 2022606
• 负责人: ROBERT S COLEMAN
• 金额: $ 10.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2022606
• 关键词: DNA damage; alkylation; antisense nucleic acid; complementary DNA; crosslink; drug design /synthesis /production; gene expression; nucleic acid chemical synthesis; nucleic acid probes; oligonucleotides; polynucleotides; synthetic nucleic acid

Inhibition of genetic expression by the direct interaction of probe molecules with specifically targeted sequences of DNA or mRNA is a fundamental approach to the chemotherapeutic treatment of viral and oncogenic diseases. Selective inhibition of gene expression using antisense oligonucleotides exploits the base-pairing capability of DNA or mRNA to escort the antisense probe to a targeted sequence of nucleic acids, thereby making this approach to chemotherapy exceptionally specific. The studies described in this proposal use a "modified nucleic acid" strategy for template-directed covalent alkylation of DNA. This process will be achieved by the chemical synthesis of suitably functionalized modified nucleic acids, the incorporation of these bases into oligonucleotides, and the post-synthetic attachment of an electrophilic tether. Upon duplex formation with a complementary oligonucleotide strand, a covalent cross-link will be formed between the probe oligonucleotide and a nucleophilic group on the complementary strand. The consequence of this process will be the creation of an indelible lesion that will irreversibly mask the genetic information contained within the targeted oligonucleotide molecule. Such covalent oligonucleotide probes could provide the basis for a valuable new class of highly specific pharmacological agents for antisense inhibition of oncogenic, genetic, and viral diseases.

通过探针的直接相互作用抑制遗传表达 具有特定靶向DNA或mRNA的靶向序列的分子为A 对病毒和化学治疗的基本方法 致癌性疾病。选择性抑制基因表达 反义寡核苷酸利用DNA或 mRNA护​​送反义探针到靶向的核序列 酸，从而使这种化疗方法异常 具体的。 该提案中描述的研究使用“改良的核酸” DNA的模板定向共价烷基化策略。这个过程 将通过适当功能化的化学合成来实现 修饰的核酸，将这些碱掺入到 寡核苷酸和亲电的合成后附着 系绳。双链形成互补的寡核苷酸链时， 探针寡核苷酸和 互补链上的亲核群。结果的结果 过程将是不可逆转的不可逆转的病变 掩盖靶向寡核苷酸中包含的遗传信息 分子。这种共价寡核苷酸探针可以为 有价值的新型高度特定的药理学剂 反义抑制致癌，遗传和病毒疾病。