OLIGONUCLEOTIDE ANALOGS AS ANTIVIRAL/ANTICANCER AGENTS

这个项目的目标只有一个--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/抗癌药物 治疗剂。这款模拟器之间的唯一区别是 而脱氧寡核苷酸是类似物的主干 由非离子甲基膦酸键组成，而不是 负的磷酸二酯键。这些类比完全是 抵抗核酸酶；被哺乳动物细胞摄取；来自 具有互补性的稳定的序列特异性双链 RNA单链区域；并选择性地抑制 细胞内靶向信使核糖核酸的功能和剪接这些类比 从而为特定基因提供了一条特异的“遮蔽带” 表达，被称为“马特根”。先前的研究表明 序列特异性Matagens特异性抑制珠蛋白 网织红细胞、水泡性口炎病毒的合成 小鼠L细胞的复制和病毒蛋白合成，以及 在猴细胞中合成SV-40大T抗原以及 单纯疱疹病毒的复制和即刻表达 Vero或人类细胞中的早期基因。因此，这些马塔根人可以 在不影响宿主细胞的情况下抑制病毒复制。 Matagens将使用以下终端附件进行修改 补骨脂素和这种修饰的Matagens可以与 靶向RNA以双链形式形成，并在近紫外线照射下。 Matagens还将使用一个终端附件进行修改 Fe+-螯合基团(如EDTA)，它允许 氧化还原反应中氧自由基的产生。这个 因此，Matgen-EDTA可以割裂目标的脊梁 当形成一个双链时，它就会被转录成mrna。本计划项目包括 约翰大学保罗·S·米勒博士领导的一个化学小组 由迈克尔博士领导的药理学/毒性研究小组 约翰·霍普金斯大学的科尔文；由 劳尔·奥雷利安博士，马里兰大学医学院 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； 由Uniform的Esther Chang博士领导的癌基因小组 服务大学，以及由 兼任校长的Paul O.P.To博士 调查员。科学核心项目由Dr。 保罗·米勒，他也将担任联合首席调查员。 将提供Matgen作为病毒基因的特异性抑制物 以下病毒的功能：单纯疱疹病毒2型、巨细胞病毒 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。这项研究是 旨在为Matgen在中国的临床试验做准备 不久的将来。

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.