Naesens L, Lenaerts L, Andrei G, Snoeck R, Van Beers D, Holy Antonin, Balzarini Jan, De Clercq Erik
Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Antimicrob Agents Chemother. 2005 Mar;49(3):1010-6. doi: 10.1128/AAC.49.3.1010-1016.2005.
The absence of any formally licensed antiadenovirus drugs and the increasing incidence of life-threatening adenovirus infections in immunosuppressed patients warrant the development of effective antiadenovirus compounds. A detailed study was performed on the antiadenovirus activities of several classes of nucleoside and nucleotide analogues in human embryonic lung fibroblast cells. The antiadenovirus activities were evaluated by three methods, viz., evaluating the adenoviral cytopathic effect, monitoring cell viability by a colorimetric assay, and real-time PCR quantitation of viral DNA as a direct parameter for virus replication. The most active and selective compounds were the acyclic nucleoside phosphonate analogues cidofovir, its adenine analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], and the new derivative (S)-2,4-diamino-6-[3-hydroxy-2-(phosphonomethoxy)propoxy]pyrimidine [(S)-HPMPO-DAPy]; the N7-substituted acyclic derivative 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine (S-2242); and the 2',3'-dideoxynucleoside analogues zalcitabine and alovudine. No antiadenovirus activity was observed for the antiviral drugs ribavirin, foscarnet, acyclovir, penciclovir, and brivudin, while ganciclovir displayed modest activity. However, in human osteosarcoma cells transfected with herpes simplex virus thymidine kinase, ganciclovir demonstrated highly potent antiadenovirus activity, suggesting that the efficacy of ganciclovir against adenovirus is limited by inefficient phosphorylation in adenovirus-infected cells, rather than by insufficient inhibition at the viral DNA polymerase level. Collectively, our antiviral data show that the adenovirus DNA polymerase exhibits sensitivity to a relatively broad spectrum of inhibitors and should be studied further as an antiviral target in antiadenovirus drug development programs.
由于缺乏任何正式获批的抗腺病毒药物，且免疫抑制患者中危及生命的腺病毒感染发病率不断上升，因此有必要研发有效的抗腺病毒化合物。我们对几类核苷和核苷酸类似物在人胚肺成纤维细胞中的抗腺病毒活性进行了详细研究。通过三种方法评估抗腺病毒活性，即评估腺病毒细胞病变效应、用比色法监测细胞活力以及通过实时PCR定量病毒DNA作为病毒复制的直接参数。活性和选择性最强的化合物是无环核苷膦酸类似物西多福韦、其腺嘌呤类似物（S）-9-（3-羟基-2-膦酰甲氧基丙基）腺嘌呤[（S）-HPMPA]以及新衍生物（S）-2,4-二氨基-6-[3-羟基-2-（膦酰甲氧基）丙氧基]嘧啶[（S）-HPMPO-DAPy]；N7-取代的无环衍生物2-氨基-7-（1,3-二羟基-2-丙氧基甲基）嘌呤（S-2242）；以及2'，3'-二脱氧核苷类似物扎西他滨和阿洛苷。抗病毒药物利巴韦林、膦甲酸钠、阿昔洛韦、喷昔洛韦和布立伏定未观察到抗腺病毒活性，而更昔洛韦表现出适度活性。然而，在转染了单纯疱疹病毒胸苷激酶的人骨肉瘤细胞中，更昔洛韦表现出高效的抗腺病毒活性，这表明更昔洛韦对腺病毒的疗效受腺病毒感染细胞中磷酸化效率低下的限制，而非病毒DNA聚合酶水平抑制不足。总体而言，我们的抗病毒数据表明，腺病毒DNA聚合酶对相对广泛的抑制剂敏感，应在抗腺病毒药物研发项目中作为抗病毒靶点进一步研究。
