1-β-D-阿拉伯呋喃糖基-5-氟尿嘧啶对人巨细胞病毒复制的选择性抑制机制
Mechanism of selective inhibition of human cytomegalovirus replication by 1-beta-D-arabinofuranosyl-5-fluorouracil.
作者信息
Suzuki S, Saneyoshi M, Nakayama C, Nishiyama Y, Yoshida S
出版信息
Antimicrob Agents Chemother. 1985 Aug;28(2):326-30. doi: 10.1128/AAC.28.2.326.
Four kinds of 1-beta-D-arabinofuranosyl-5-halogenouracil were examined for inhibition of human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) replication. 1-beta-D-Arabinofuranosyl-5-fluorouracil (ara-FU) was the most effective against HCMV, whereas 1-beta-D-arabinofuranosyl-5-bromouracil was the most effective against HSV-1 and HSV-2. The mechanism of action of ara-FU on HCMV replication was also studied. The dTTP pool size in human embryonic fibroblasts was increased 33-fold by HCMV infection. However, treatment with ara-FU decreased the size of the dTTP pool by approximately 50%. On the other hand, 1-beta-D-arabinofuranosyl-5-fluorouracil-5'-triphosphate inhibited HCMV DNA polymerase activity competitively with dTTP. These results suggest that ara-FU acts as a bifunctional inhibitor of HCMV replication. Ara-FU is phosphorylated by cellular thymidine kinase to 1-beta-D-arabinofuranosyl-5-fluorouracil-5'-monophosphate, which inhibits cellular thymidylate synthetase, which in turn decreases the dTTP pool size in infected cells. As the dTTP pool size is reduced, inhibition of viral DNA polymerase by 1-beta-D-arabinofuranosyl-5-fluorouracil-5'-triphosphate becomes more efficient.
研究了四种1-β-D-阿拉伯呋喃糖基-5-卤代尿嘧啶对人巨细胞病毒（HCMV）以及单纯疱疹病毒1型（HSV-1）和2型（HSV-2）复制的抑制作用。1-β-D-阿拉伯呋喃糖基-5-氟尿嘧啶（ara-FU）对HCMV最有效，而1-β-D-阿拉伯呋喃糖基-5-溴尿嘧啶对HSV-1和HSV-2最有效。还研究了ara-FU对HCMV复制的作用机制。HCMV感染使人类胚胎成纤维细胞中的dTTP池大小增加了33倍。然而，用ara-FU处理使dTTP池大小减少了约50%。另一方面，1-β-D-阿拉伯呋喃糖基-5-氟尿嘧啶-5'-三磷酸与dTTP竞争性抑制HCMV DNA聚合酶活性。这些结果表明ara-FU作为HCMV复制的双功能抑制剂发挥作用。Ara-FU被细胞胸苷激酶磷酸化为1-β-D-阿拉伯呋喃糖基-5-氟尿嘧啶-5'-单磷酸，后者抑制细胞胸苷酸合成酶，进而降低感染细胞中的dTTP池大小。随着dTTP池大小的减少，1-β-D-阿拉伯呋喃糖基-5-氟尿嘧啶-5'-三磷酸对病毒DNA聚合酶的抑制变得更有效。
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