OLIGONUCLEOTIDE ANALOGS AS ANTIVIRAL/ANTICANCER AGENTS

这个项目只有一个目标：发展 以及非离子脱氧寡核苷酸类似物作为 科学研究中的探针和作为抗病毒/抗癌 治疗剂。 这个模拟器和 而脱氧寡核苷酸是类似物的骨架 由非离子甲基膦酸酯键组成， 负磷酸二酯键。 这些类似物完全是 抗核酸酶;被哺乳动物细胞吸收;从 稳定的序列特异性双链体， RNA的单链区域;并选择性地抑制 细胞中靶向mRNA的功能和剪接。 这些类似物 从而作为特定基因特异性“遮蔽带 表达，称为“Matagen”。 以前的研究表明 序列特异性Matagen特异性抑制珠蛋白 网织红细胞合成，水泡性口炎病毒 小鼠L细胞中的病毒复制和病毒蛋白合成，以及 猴细胞中SV-40大T抗原的合成，以及 单纯疱疹病毒复制与即刻表达 Vero或人类细胞中的早期基因。 因此，这些Matagens可以 抑制病毒复制而不影响宿主细胞。 Matagens将被修改为末端连接 peptide和这种改性的Matagen可以与交联剂交联。 靶向RNA在双链体形成和近UV照射后的表达。 Matagens也将被修饰为末端连接一个 Fe++-螯合基团（如EDTA），其允许 在氧化还原反应中产生氧自由基。 的 因此，Matagen-EDTA可以切割靶向的 mRNA在形成双链体时的表达。 本项目由 一个化学小组的负责人是保罗·S。米勒在约翰 霍普金斯;由Michael博士领导的药理学/毒性小组 科尔文在约翰霍普金斯;一个单纯疱疹病毒小组领导的 博士马里兰州医学院的Laure Aurelian 人类T细胞白血病病毒III（HTLV-III）组， 由康奈尔医学中心的杰弗里·劳伦斯博士领导; 一个由制服警察局的Esther Chang博士领导的致癌基因小组 服务大学，以及由 博士曹国伟，他也是校长 调查员 科学核心项目由博士领导。 Paul米勒，他也将担任共同主要研究者。 Matagen将作为病毒基因的特异性抑制剂提供 以下病毒的功能：HSV-2、巨细胞病毒 (CMV)SV-40; HTLV-III;以及动物肿瘤中的癌基因 模型和叙利亚仓鼠胚胎细胞。 本研究 旨在为Matagen的临床试验做准备， 近期

This Program Project has only one objective -- the development and application of nonionic deoxyoligonucleotide analogs as probes in scientific studies and as antivirus/anticancer therapeutic agents. The only difference between this analog and the deoxyoligonucleotide is that the backbone of the analog consists of the nonionic methylphosphonate linkage instead of the negative phosphodiester linkage. These analogs are totally resistant to nucleases; are taken up by mammalian cells; from stable, sequence-specific duplexes with complementary single-stranded regions of RNA; and selectively inhibit the function and splicing of targeted mRNA in cells. These analogs thus serve as specific "masking tape" for specific gene expression, termed as "Matagen". Previous studies show sequence-specific Matagens specifically inhibit globin synthesis in reticulocytes, Vesicular stomatitis virus replication and viral protein synthesis in mouse L cells, and SV-40 large T antigen synthesis in monkey cells, as well as Herpes simplex virus replication and expression of immediate early genes in Vero or human cells. Thus, these Matagens can inhibit viral replication without affecting the host cells. The Matagens will be modified with a terminal attachment of psoralen and such modifed Matagens can crosslink with the targeted RNA in duplex formation and upon near UV irradiation. Matagens will also be modified with a terminal attachment of a Fe++-chelating group (such as EDTA), which allows the generation of oxygen free radicals in a redox reaction. The Matagen-EDTA can therefore cleave the backbone of the targeted mRNA upon formation of a duplex. This Program Project consists of a Chemistry Group headed by Dr. Paul S. Miller at John Hopkins; a Pharmacology/Toxicity Group headed by Dr. Michael Colvin at Johns Hopkins; a Herpes Simplex Virus Group headed by Dr. Laure Aurelian at the University of Maryland Medical School; a Human T-Cell Leukemia Virus III (HTLV-III) Group, headed by Dr. Jeffrey Laurence at the Cornell Medical center; an Oncogene Group headed by Dr. Esther Chang of the Uniformed Services University, and a Molecular Cytology Group headed by Dr. Paul O.P. Ts'o, who also serves as the Principal Investigator. The Scientific Core Project is headed by Dr. Paul Miller, who will also serve as Co-Principal Investigator. Matagen will be provided as specific suppressors of viral gene function of the following viruses: HSV-2, cytomegalovirus (CMV); SV-40; HTLV-III; as well as oncogenes in animal tumor models and in Syrian hamster embryo cells. This study is intended to prepare for the clinical trial of Matagen in the near future.