Juan Ella Czarina Magat, Kurihara Takeshi, Kondo Jiro, Ito Takanori, Ueno Yoshihito, Matsuda Akira, Takénaka Akio
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Midori-ku, Yokohama 226-8501, Japan.
Nucleic Acids Symp Ser (Oxf). 2004(48):305-6. doi: 10.1093/nass/48.1.305.
Oligonucleotides containing polyamines are currently being evaluated as potential antigene compounds for therapeutic purposes. Among them, 5-(N-aminohexyl) carbamoyl-2'-deoxyuridine ((N)U) and 5-(N-aminohexyl) carbamoyl-2'-O-methyluridine ((N)Um) substituted oligonucleotides have higher resistance against nuclease degradation compared to native DNA. Furthermore, oligonucleotides containing (N)U stabilizes duplex formation with the complementary DNA. To elucidate the mechanisms behind these improved antigene properties, we synthesized and crystallized two Dickerson-Drew-type DNA duplexes containing (N)U and (N)Um. The 2'-O-methyl modification in (N)Um was found to induce the ribose ring to adopt the C3'-endo conformation. Electron density maps show possible interactions of the terminal ammonium ion of the aminohexyl groups with the phosphate oxygen anions.
目前，含有多胺的寡核苷酸正在作为潜在的治疗性反基因化合物进行评估。其中，5-(N-氨基己基)氨基甲酰基-2'-脱氧尿苷((N)U)和5-(N-氨基己基)氨基甲酰基-2'-O-甲基尿苷((N)Um)取代的寡核苷酸与天然DNA相比，对核酸酶降解具有更高的抗性。此外，含有(N)U的寡核苷酸能稳定与互补DNA的双链体形成。为了阐明这些改善的反基因特性背后的机制，我们合成并结晶了两种含有(N)U和(N)Um的Dickerson-Drew型DNA双链体。发现(N)Um中的2'-O-甲基修饰会诱导核糖环采取C3'-内型构象。电子密度图显示了氨基己基末端铵离子与磷酸氧阴离子之间可能的相互作用。
