Chapter 3fRNA糖药物.pptVIP

作用于RNA的氨基糖苷类 抗生素的改性 (选自北京大学药学院叶新山教授的报告) 基因组 / 蛋白组 / 糖组 RNA作为遗传信息的携带传递 者，执行重要的生物功能，但就其 化学结构而言，由四个平面碱基组 成，每个核苷带有负电荷，长期以 来并不是被人们看好的靶点。随着 X射线单晶衍射及核磁技术的发展， 发现RNA象蛋白一样，可以折叠成 复杂的三维结构，从而为小分子特 异的与RNA结合提供了可能。 Chem.Biol. 1998,5:R277-R283 以RNA为靶的药物研究 X-ray crystal structure of A site binding with paromomycin NATURE,VOL 407 ,340 Structure of A site binding with paromomycin determinated by NMR SCIENCE,VOL 274 ,1367 RNA的结构 siRNA是明星分子 siRNA in Bioscience Research Small interfering RNA (siRNA) is a tool that is revolutionizing bioscience research. The increased use of siRNA in peer reviewed publications clearly demonstrates that it is an incredibly powerful means to specifically knock-down a genes message, and subsequently the protein level of the targeted gene. In this manner, cellular-based assays can be conducted in the absence and presence of the targeted genes protein.  The value of such an experiment has long been known as researchers the world over have employed genetic knock-out technologies, dominant negatives and chemical inhibitors of protein activities to perform such experiments. The use of siRNA is replacing all three of these methodologies. siRNA是明星分子 某些与RNA作用的小分子配体 Gentamycin Kanamycin Lividomycin Monomycin Neamine Ribostamycin 氨基糖苷类抗生素示例 氨基糖苷类抗生素的缺点: 通常口服无效, 只能局部给药或注射给药; 剂量大时损害听力和肾脏; 耐药性问题日益严重。 Ye, X.-S.; Zhang, L.-H. Curr. Med. Chem. 2002, 9, 929. 氨基糖苷类抗生素与RNA的相互作用 与核糖体RNA的作用 1: Kd = 1.7 μM; 2: Kd = 0.26 μM 与核糖体RNA的作用 组合化学途径 Pyranmycins, a Novel Class of Aminoglycosides with Improved stability: The SAR of D-Pyranoses on Ring III of Pyranmycin Cheng-Wei Tom Chang,* Yu Hui, Bryan Elchert, Jinhua Wang, Jie Li, and Ravi Rai Angew. Chem. Int. Ed. 2003, 42, 3409 – 3412