TEMPLATE DIRECTED COVALENT CROSS LINKING OF DNA

利用探针的直接相互作用抑制基因表达 具有特定靶向DNA或mRNA序列的分子是一种 病毒性肝炎化疗的基本途径 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 信使核糖核酸护送反义探针至靶向核序列 酸，从而使这种化疗方法变得异常 具体的。 这项建议中描述的研究使用了一种“修饰核酸”。 模板导向的DNA共价烷基化策略。这一过程 将通过化学合成来实现适当的功能化 修饰的核酸，将这些碱基掺入 寡核苷酸和一种亲电性的后合成附着物 系绳。当与互补的寡核苷酸链形成双链时， 探针寡核苷酸和探针之间将形成共价交联。 互补链上的亲核基团。这样做的后果是 这一过程将会造成不可逆转的损害 掩蔽目标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 一类有价值的高度特异的治疗药物 反义抑制致癌、遗传和病毒疾病。

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.