Metabolism of Cyclopropavir and Ganciclovir in Human Cytomegalovirus-Infected Cells
Metabolism of Cyclopropavir and Ganciclovir in Human Cytomegalovirus-Infected Cells
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DOI：
10.1128/aac.02311-13
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发表时间：
2014-04-01
影响因子：
4.9
通讯作者：
Drach, John C.
中科院分区：
文献类型：
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作者：
Gentry, Brian G.;Drach, John C.
人巨细胞病毒（HCMV）是一种广泛存在的病原体，可在免疫不成熟和免疫功能低下的患者中引起严重疾病。目前治疗HCMV感染的标准疗法是更昔洛韦（GCV）。然而，不良反应的高发生率是普遍的，并限制了这种药物的使用。环丙帕韦（CPV）在体外抗HCMV的有效性比GCV高10倍（50%有效浓度[EC（50）s]分别为0.46和4.1 μ M），而没有观察到细胞毒性的任何增加（S. Zhou，J. M. Breitenbach，K. Z. Borysko，J. C. Drach，E. R.克恩，E. Gullen，Y. C. Cheng和J. Zemlicka，J.Med.Chem.47：566-575，2004，doi：10.1021/jm030316s）。我们先前已经确定，病毒蛋白激酶pUL 97和内源性细胞激酶负责将CPV转化为三磷酸（TP），三磷酸是负责抑制病毒DNA合成和病毒复制的活性化合物。然而，在HCMV感染的细胞中没有观察到这种转化。为此，我们将HCMV感染的细胞置于等效有效浓度（类似于EC 50的5倍）的CPV或GCV中，并观察到两种化合物的三磷酸水平呈时间依赖性增加（CPV-TP = 121 +/- 11 pmol/106个细胞; GCV-TP = 43.7 +/- 0.4 pmol/10（6）个细胞）。观察到GCV-TP的半衰期（48.2 +/- 5.7小时）长于CPV-TP（23.8 +/- 5.1小时）。用2.5 μ M CPV孵育产生的CPV-TP曲线下面积为8，680 +/- 930 pmol.h/10（6）个细胞，约为用25 μ M GCV孵育产生的GCV-TP曲线下面积4，520 +/- 420 pmol.h/10（6）个细胞的2倍。因此，我们得出结论，在这些实验条件下，HCMV感染的细胞暴露于CPV-TP大于GCV-TP。
Human cytomegalovirus (HCMV) is a widespread pathogen that can cause severe disease in immunologically immature and immunocompromised patients. The current standard of therapy for the treatment of HCMV infections is ganciclovir (GCV). However, high incidence rates of adverse effects are prevalent and limit the use of this drug. Cyclopropavir (CPV) is 10-fold more effective against HCMV in vitro than GCV (50% effective concentrations [EC(50)s] = 0.46 and 4.1 mu M, respectively) without any observed increase in cytotoxicity (S. Zhou, J. M. Breitenbach, K. Z. Borysko, J. C. Drach, E. R. Kern, E. Gullen, Y. C. Cheng, and J. Zemlicka, J. Med. Chem. 47: 566-575, 2004, doi: 10.1021/jm030316s). We have previously determined that the viral protein kinase pUL97 and endogenous cellular kinases are responsible for the conversion of CPV to a triphosphate (TP), the active compound responsible for inhibiting viral DNA synthesis and viral replication. However, this conversion has not been observed in HCMV-infected cells. To that end, we subjected HCMV-infected cells to equivalently effective concentrations (similar to 5 times the EC50) of either CPV or GCV and observed a time-dependent increase in triphosphate levels for both compounds (CPV-TP = 121 +/- 11 pmol/106 cells; GCV-TP = 43.7 +/- 0.4 pmol/10(6) cells). A longer half-life was observed for GCV-TP (48.2 +/- 5.7 h) than for CPV-TP (23.8 +/- 5.1 h). The area under the curve for CPV-TP produced from incubation with 2.5 mu M CPV was 8,680 +/- 930 pmol.h/10(6) cells, approximately 2-fold greater than the area under the curve for GCV-TP of 4,520 +/- 420 pmol.h/10(6) cells produced from incubation with 25 mu M GCV. We therefore conclude that the exposure of HCMV-infected cells to CPV-TP is greater than that of GCV-TP under these experimental conditions.