https://scholars.lib.ntu.edu.tw/handle/123456789/638323
標題: | Deoxycytidine deaminase-resistant stereoisomer is the active form of (+/-)-2',3'-dideoxy-3'-thiacytidine in the inhibition of hepatitis B virus replication | 作者: | Chang, C N SHIN-LIAN DOONG Zhou, J H Beach, J W Jeong, L S Chu, C K Tsai, C H Cheng, Y C Liotta, D Schinazi, R |
公開日期: | 15-七月-1992 | 卷: | 267 | 期: | 20 | 來源出版物: | The Journal of biological chemistry | 摘要: | 2',3'-Dideoxy-3'-thiacytidine (+/-)-SddC) was found to have potent activity against human hepatitis B virus as well as human immunodeficiency viruses in culture. The (-)form ((-)-SddC) which is resistant to deoxycytidine deaminase was found to be the more active antiviral stereoisomer than the (+)-form ((+)-SddC). The (+)-SddC is susceptible to deamination by deoxycytidine deaminase and is 25- and 12-fold more toxic than (-)-SddC in CEM cells in terms of anti-cell growth and anti-mitochondrial DNA synthesis, respectively. Similar results were obtained using a mixture of their 5-fluoro analogs ((+/-)-FSddC). Unlike 2',3'-dideoxycytidine, which is a potent inhibitor of mitochondrial DNA synthesis and results in such delayed toxicity as peripheral neuropathy with long term usage, (-)-SddC does not affect mitochondrial DNA synthesis. The (-)form is phosphorylated to (-)-SddCMP and is subsequently converted to (-)-SddCDP and (-)-SddCTP. One additional major metabolite which has been tentatively assigned the name "(-)-SddCMP sialate" was also identified. No significant difference in terms of the profiles of the metabolites was found between 4 and 24 h. There is an appreciable amount of (-)-SddCTP detectable 24 h after removal of the drug. (-)-SddCTP was also found to be approximately 3-fold more potent than (+)-SddCTP in inhibiting human hepatitis B virus DNA polymerase. This is the first nucleoside analog with the unnatural sugar configuration demonstrated to have antiviral activity. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/638323 | ISSN: | 0021-9258 |
顯示於: | 微生物學科所 |
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