Ribonucleotide reductase inhibitors hydroxyurea, didox, and trimidox inhibit human cytomegalovirus replication in vitro and synergize with ganciclovir
Ribonucleotide reductase inhibitors hydroxyurea, didox, and trimidox inhibit human cytomegalovirus replication in vitro and synergize with ganciclovir
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DOI：
10.1016/j.antiviral.2013.07.016
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发表时间：
2013-10-01
影响因子：
7.6
通讯作者：
McVoy, Michael A.
中科院分区：
文献类型：
--
作者：
Bhave, Sukhada;Elford, Howard;McVoy, Michael A.
更昔洛韦（GCV）是一种脱氧鸟苷类似物，可有效抑制人巨细胞病毒（HCMV）复制。在受感染的细胞中，GCV被转化为GCV-三磷酸，其与dGTP竞争通过病毒DNA聚合酶掺入生长的DNA链中。合并的GCV促进链终止，因为它是一种低效的延伸底物。由于病毒DNA合成也依赖于细胞核糖核苷酸还原酶（RR）来合成脱氧核苷酸，因此预计RR抑制剂可抑制HCMV复制。此外，由于dGTP与GCV-三磷酸竞争掺入，RR抑制剂也可通过降低细胞内dGTP水平并促进DNA聚合酶对GCV-三磷酸的利用而与GCV协同作用。为了研究RR抑制剂单独和与GCV组合作为抗HCMV剂的潜力，测定了三种RR抑制剂（羟基脲、didox和trimidox）的HCMV抑制活性。在扩散抑制和产量降低试验中，RR抑制剂具有适度的抗HCMV活性，50%抑制浓度范围为36 +/- 1.7至221 +/- 52 μ M。然而，所有这三种药物在低于其50%抑制浓度和50%毒性浓度的浓度下与GCV显示出显著的协同作用。这些结果表明，将GCV与相对低剂量的RR抑制剂组合可以显著增强GCV的体内抗HCMV活性，并且可以改善对治疗的临床应答。(C)2013爱思唯尔有限公司版权所有。
Ganciclovir (GCV) is a deoxyguanosine analog that is effective in inhibiting human cytomegalovirus (HCMV) replication. In infected cells GCV is converted to GCV-triphosphate which competes with dGTP for incorporation into the growing DNA strand by the viral DNA polymerase. Incorporated GCV promotes chain termination as it is an inefficient substrate for elongation. Because viral DNA synthesis also relies on cellular ribonucleotide reductase (RR) to synthesize deoxynucleotides, RR inhibitors are predicted to inhibit HCMV replication. Moreover, as dGTP competes with GCV-triphosphate for incorporation, RR inhibitors may also synergize with GCV by reducing intracellular dGTP levels and there by promoting increased GCV-triphosphate utilization by DNA polymerase. To investigate potential of RR inhibitors as anti-HCMV agents both alone and in combination with GCV, HCMV-inhibitory activities of three RR inhibitors, hydroxyurea, didox, and trimidox, were determined. In both spread inhibition and yield reduction assays RR inhibitors had modest anti-HCMV activity with 50% inhibitory concentrations ranging from 36 +/- 1.7 to 221 +/- 52 mu M. However, all three showed significant synergy with GCV at concentrations below their 50% inhibitory and 50% toxic concentrations. These results suggest that combining GCV with relatively low doses of RR inhibitors could significantly potentiate the anti-HCMV activity of GCV in vivo and could improve clinical response to therapy. (C) 2013 Elsevier B.V. All rights reserved.