Preparation of Artificial Ribonucleases and Their Applications to the Therapy for Cancer and AIDS

人工核糖核酸酶的制备及其在癌症和艾滋病治疗中的应用

• 批准号: 08559005
• 负责人: KOMIYAMA Makoto
• 金额: $ 2.05万
• 依托单位: Graduate School of Engineering, The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08559005/
• 关键词: RNA; Hydrolysis; Oligoamine; Artificial ribonuclease; Cancer; AIDS; Therapy; アミン

With the aims to develop new therapeutic methods for cancer and AIDS,artificial ribonucleases have been prepared, and RNA scission mechanism is investigated. It is confirmed that intramolecular acid/base cooperation is responsible for the remarkable catalysis of oligoamines for RNA hydrolysis. Novel artificial ribonucleases in which oligoamines are attached inside of DNA oligomers (which are complementary with a part of the substrate RNA) have been synthesized. These artificial enzymes cut the target RNA more precisely than the ones with the scissors at the ends of DNA oligomers, mainly because the scissors are fixed in the rigidly structured double strands. Furthermore, Conjugates of an intercalator and either glycine or iminodiacetate show effective scission of RNA.These conjugates are neutral or negatively charged, which is highly in contrast with the fact that the previously reported RNA scissors are positively charged. Thus, they can be placed exactly at the desired site, even in a strong electrostatic field induced by RNA.These artificial ribonucleases cleave only the target RNA in cells, and thus should be highly potent for the therapy of cancer and AIDS.

为了开发针对癌症和艾滋病的新治疗方法，已经制定了人造核糖核酸酶，并研究了RNA分裂机制。据证实，分子酸/碱基的合作是寡胺的显着催化RNA水解。已合成了在DNA低聚物内（与底物RNA的一部分互补）内附着的新型人工核糖核酸酶。这些人工酶比在DNA低聚物末端的剪刀更精确地切割了靶RNA，这主要是因为剪刀固定在刚性结构的双链中。此外，插盐剂和甘氨酸或二甲酸酯的偶联物显示出有效的RNA。这些结合物是中性或负电荷的，这与先前报道的RNA剪刀具有正相反的是高电荷。因此，即使是由RNA诱导的强静电场，它们也可以精确地放置在所需的位置上。这些人造核糖核酸酶仅裂解细胞中的靶RNA，因此对于癌症和艾滋病的治疗应该非常有效。

项目成果

M.Endo et al.: "RNA hydrolysis by the cooperation of carboxylate ion and ammonium ion" J.Am.Chem.Soc.118. 5478-5479 (1996)

M.Endo 等人：“通过羧酸根离子和铵离子的合作进行 RNA 水解”J.Am.Chem.Soc.118。

Masaki Endo et al.: "Novel phosphoramidite monomer for the site-selective incorporation of a diastereochemically pure phosphoramidate to oligo-nucleotide." J.Org.Chem.61(6). 1994-2000 (1996)

Masaki Endo 等人：“用于将非对映化学纯的氨基磷酸酯位点选择性掺入寡核苷酸的新型亚磷酰胺单体。”

M.Endo, Y.Azuma, Y.Saga, A.Kuzuya, G.Kawai, and M.Komiyama: ""Molecular design for a pinpoint RAN scission. Interposition of oligoamines between two DNA oligomers."" J.Org.Chem.62(4). 846-852 (1997)

M.Endo、Y.Azuma、Y.Saga、A.Kuzuya、G.Kawai 和 M.Komiyama：“”精确 RAN 断裂的分子设计。

M.Endo et al.: "Molecular design for a pinpoint RNA scission.Interposition of oligoamine between two DNA oligomers." J.Org.Chem. (in press).

M.Endo 等人：“精确 RNA 断裂的分子设计。在两个 DNA 寡聚物之间插入寡胺。”

M.Endo, Y.Azuma, and M.Komiyama: ""Site-selective RNA hydrolysis by a novel artificial ribo-nuclease : Interposition of oligoamine between two DNA oligomers."" Nucleic Acids, Symp.Ser.35. 81-82 (1996)

M.Endo、Y.Azuma 和 M.Komiyama：“通过新型人工核糖核酸酶进行位点选择性 RNA 水解：在两个 DNA 寡聚物之间插入寡胺。”《核酸》，Symp.Ser.35。