Chapter3fRNA糖药物

1、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,pa

2、romomycin,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 pub

3、lications 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 s

4、uch 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

5、体,Gentamycin,Kanamycin,Lividomycin,Monomycin,Neamine,Ribostamycin,氨基糖苷类抗生素示例,O,R,2,NH,3,HO,R,1,O,+,OH,R,3,HN,NH,2,R,4,+,O,OH,O,OH,O,O,H,3,N,OH,O,NH,3,+,+,O,OH,OH,HO,OH,I,II,III,IV,V,Neamine,Ribostamycin,Neomycin B,Paromomycin I,Lividomycin A,NH,3,OH,H,H,+,NH,3,OH,H,H,+,NH,3,OH,H,H,+,OH,H,H,OH,H,H,H,

6、OH,R,1,R,2,R,3,R,4,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.,G,C,C,A,C,A,A,C,U,C,G,G,C,U,U,C,G,A,A,A,C,G,A,U,C,G,C,G,1410,1490,1495,1406,1500,1400,E. Coli.,16S,Ribosomal RNA,C,G,G,C,U,U,C,G,A,A,A,C,G,A,U,C,G,C,G,1410,1490,1495,1

7、406,G,C,G,C,U,G,U,C,C,G,G,C,U,A,C,G,A,A,A,C,G,A,U,C,G,C,G,1410,1490,1495,1406,G,C,G,C,U,G,U,C,AS-wt,AS-U1495A,氨基糖苷类抗生素与,RNA,的相互作用,O,HO,NH,2,HO,NH,2,O,OH,H,2,N,NH,2,O,OH,O,OH,O,R,1,: R =,3,: R =,2,: R =,4,: R =,H,2,N,H,2,N,H,N,O,OH,OH,HO,OH,O,OH,OH,H,2,N,OH,与核糖体,RNA,的作用,1: Kd = 1.7,M; 2: Kd = 0.26,M,

8、O,HO,NH,2,HO,NH,2,O,OH,H,2,N,NH,2,O,R,H,2,N,H,N,H,2,N,N,H,N,H,2,N,N,NH,2,N,N,H,2,N,O,N,H,N,H,2,N,H,N,OH,H,2,N,H,N,OH,HO,H,N,OH,N,H,N,H,N,R =,11,12,13,14,15,16,17,18,19,与,核,糖,体,RNA,的,作,用,O,HO,NH,HO,NH,2,O,N,H,: variable,O,HO,H,2,N,HO,N,3,O,Acylation,Reductive,Amination,R,1,R,2,组合化学途径,Pyranmycins, a N

9、ovel 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,O,HO,NH,2,HO,NH,2,O,OH,H,2,N,NH,2,O,R,O,NH,NH,OH,NH,NH,OMe,NH,H,3,C,NH,F,NH

10、,MeO,N,H,NH,OH,CH,3,NH,22,23,24,25,26,27,28,29,30,31,与信使,RNA,的作用,有可能抑制癌基因,RNA,的转录,O,HO,NH,2,HO,NH,2,O,OH,H,2,N,NH,2,O,R,N,N,H,N,NH,NH,NH,N,H,NH,N,NH,N,NH,NH,NH,N,NH,N,H,N,NH,32,(4:5:1),33,34,35,36,(1:3),37,与信使,RNA,的作用,O,HO,NH,2,HO,NH,2,O,OH,H,2,N,NH,2,O,O,O,O,NH,2,OH,HO,H,2,N,HO,S,O,HO,NH,2,HO,O,OH,

11、H,2,N,NH,2,O,O,O,O,NH,2,OH,HO,H,2,N,HO,O,S,S,O,S,NH,2,Neo-Neo,与转移,RNA,的作用,Interact with yeast tRNA,phe,O,H,2,N,R,3,R,2,R,1,O,H,2,N,HO,NH,2,O,NH,2,R,5,R,4,H,2,N,O,1,2,4,5,6,3,2,3,4,6,5,2,3,6,4,38,Kanamycin B,OH,OH,OH,OH,OH,39,Tobramycin,OH,OH,OH,H,OH,40,4-Deoxytobramycin,OH,OH,OH,H,H,41,6-Deoxytobram

12、ycin,H,OH,OH,H,OH,42,4-Deoxytobramycin,OH,H,OH,H,OH,43,2-Deoxytobramycin,OH,OH,H,H,OH,44,6-Amino-6-deoxytobramycin,NH,2,OH,OH,H,OH,R,1,R,2,R,3,R,4,R,5,作用于催化,RNA,抑制锤头型酶性核酸的催化能力,O,HO,NH,2,HO,NH,2,O,OH,H,2,N,NH,2,O,O,O,O,NH,2,OH,HO,H,2,N,HO,HO,O,HO,NH,2,HO,NH,2,O,OH,H,2,N,NH,2,O,O,O,O,NH,2,OH,HO,H,2,N,

13、HO,N,N,H,S,Neomycin B,Neo-acridine (,45,),O,H,2,N,OH,HO,OH,O,H,2,N,HO,NH,2,O,NH,2,OH,H,2,N,O,O,OH,HO,OH,O,HN,HO,H,N,O,N,H,OH,N,H,O,H,2,N,NH,NH,2,HN,NH,2,NH,NH,H,2,N,HN,NH,H,2,N,NSO,2,CF,3,BocHN,NHBoc,46,5TFA,作用于病毒,RNA,抑制,HIV,的,Rev,蛋白,-RNA,复合物的形成,PNAS,2002,99, 11593,以,HIV-1 TAR RNA,为靶点的药物研究,O,OH,HO,N

14、H,2,O,HO,O,H,2,N,NH,2,O,OH,OH,NH,2,OH,O,O,OH,HO,NH,2,O,HO,O,H,2,N,NH,2,O,OH,OH,NH,2,OH,HO,OH,O,OH,HO,NH,2,O,HO,O,H,2,N,NH,2,O,OH,OH,NH,2,OH,O,O,H,P,O,O,O,O,P,OH,O,O,H,2,O,ATP,ADP,APH(3),Active form,Hydrated form,Unstable form,47,48,49,克服抗生素的耐药性,Mobashery,et al,.,J. Am. Chem. Soc.,1999,121, 11922.,O,BnO,N,3,BnO,N,3,O,OBn,N,3,N,3,RO,R = CH,2,CO,2,H,: neamine,N,N,O,O,R,R,linker,R,linker,H,(CH,2,),3-10,H,(CH,2,),12,H,(CH,2,),2,O(CH,2,),3,2,O,(CH,2,),12,PhCHCONHCH,2,CO,2,H,50-57,58,59,60,N,N,O