TEMPLATE DIRECTED COVALENT CROSS LINKING OF DNA

通过探针的直接相互作用抑制基因表达 具有特异性靶向DNA或mRNA序列的分子是一种 化疗治疗病毒和 致癌性疾病选择性抑制基因表达， 反义寡核苷酸利用DNA的碱基配对能力， mRNA将反义探针护送到核酸的靶序列， 酸，从而使这种方法的化疗异常 特定. 该提案中描述的研究使用了一种“修饰的核酸”， 模板指导DNA共价烷基化策略。这个过程 将通过适当官能化的 修饰的核酸，将这些碱基掺入 寡核苷酸，以及亲电子寡核苷酸的合成后连接， 拴系。在与互补寡核苷酸链形成双链体后， 探针寡核苷酸之间将形成共价交联， 互补链上的亲核基团。这样做的后果 这个过程将是一个不可磨灭的损伤， 掩蔽靶向寡核苷酸内包含的遗传信息 分子。这样的共价寡核苷酸探针可以提供基础， 一种有价值的新型高度特异性药理学试剂， 反义抑制致癌、遗传和病毒性疾病。

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.