C형 간염바이러스(HCV) 유전체를 특이적으로 변형할 수 있는 Trans-Splicing Aptazyme 발굴 = Development of Trans-Splicing Aptazyme Which Can Specifically Modify Hepatitis C Virus Genome

다국어 초록 (Multilingual Abstract)

For the development of specific and effective basic genetic materials to inhibit replication of hepatitis C virus (HCV), HCV genome-targeting trans-splicing aptazyme, which activity is allosterically regulated by a specific ligand, was developed. The aptazyme was designed to be comprised of sequence of RNA aptamer to the ligand, communication module sequence which can transfer structural transition for inducing ribozyme activity upon binding the ligand to the aptamer, and trans-splicing ribozyme targeting +199 nt of HCV IRES. Especially, when the aptamer and the communication module was inserted at both P6 and P8 catalytic domain of the specific ribozyme, allosteric activity of the aptazyme was the most induced. The aptazyme was shown to induce activity of trans-splicing reaction specifically and efficiently only in the presence of the specific ligand, but neither in the absence of any ligand nor in the presence of control ligand. This aptazyme can be used as a specific and effective genetic agent against HCV, and a tool for the isolation of anti-HCV lead compounds.

참고문헌 (Reference)

1 Pley, H.W., "model for an RNA tertiary interaction from the structure of an intermolecular complex between a GAAA tetraloop and an RNA helix" 372 : 111-113, 1994

2 Penin, F., "Structural biology of hepatitis C virus" 39 : 5-19, 2004

3 Biroccio, A., "Selection of RNA aptamers that are specific and high-affinity ligands of the hepatitis C virus RNA-dependent RNA polymerase" 76 : 3688-3696, 2002

4 Ryu, K.J, "Ribozyme-mediated selective induction of new gene activity in hepatitis C virus internal ribosome entry site-expressing cells by targeted trans-splicing" 7 : 386-395, 2003

5 Hahm, B., "NS3-4A of hepatitis C virus is a chymotrypsin-like protease" 69 : 2534-2539, 1995

6 Hwang, B., "Isolation of specific and high-affinity RNA aptamers against NS3 helicase domain of hepatitis C virus" 10 : 1277-1290, 2004

7 Choo, Q.L., "Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome" 244 : 359-362, 1989

8 Pagliaro, L., "Interferon-alpha for chronic hepatitis C: an analysis of pretreatment clinical predictors of response" 19 : 820-828, 1994

9 Kapadia, S.B., "Interference of hepatitis C virus RNA replication by short interfering RNAs" 100 : 2014-2018, 2003

10 Ali, N, "Interaction of polypyrimidine tractbinding protein with the 5' noncoding region of the hepatitis C virus RNA genome and its functional requirement in internal initiation of translation" 69 : 6367-6375, 1995

11 Chevalier, C., "Inhibition of hepatitis C virus infection in cell culture by small interfering RNAs" 15 : 1452-1462, 2007

12 Macejak, D.G., "Inhibition of hepatitis C virus (HCV)-RNA-dependent translation and replication of a chimeric HCV poliovirus using synthetic stabilized ribozymes" 31 : 769-776, 2000

13 Jenison, R.D., "High-resolution molecular discrimination by RNA" 263 : 1425-1429, 1994

14 Kolykhalov, A.A., "Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3' nontranslated region are essential for virus replication in vivo" 74 : 2046-2051, 2000

15 Saito, I., "Hepatitis C virus infection is associated with the development of hepatocellular carcinoma" 87 : 6547-6549, 1990

16 Hino, K., "Genotypes and titers of hepatitis C virus for predicting response to interferon in patients with chronic hepatitis" 42 : 299-305, 1994

17 Anwar, A., "Demonstration of functional requirement of polypyrimidine tract-binding protein by SELEX RNA during hepatitis C virus internal ribosome entry site-mediated translation initiation" 275 : 34231-34235, 2000

18 Penchovsky, R, "Computational design and xperimental validation of oligonucleotide-sensing allosteric ribozymes" 23 : 1424-1433, 2005

19 Kyung-Ju Ryu, "Comparative Analysis of Intracellular Trans-Splicing Ribozyme Activity Against Hepatitis C Virus Internal Ribosome Entry Site" 한국미생물학회 42 (42): 361-364, 2004

20 Kuo, G., "An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis" 244 : 362-364, 1989

21 Araki, M., "Allosteric regulation of a ribozyme activity through ligand-induced conformational change" 26 : 3379-3384, 1998

22 Hermann, T, "Adaptive recognition by nucleic acid aptamers" 287 : 820-825, 2000

23 Kertsburg, A, "A versitile communication module for controlling RNA folding and catalysis" 30 : 4599-4606, 2002