A PROTEIN-KINASE HOMOLOG CONTROLS PHOSPHORYLATION OF GANCICLOVIR IN HUMAN CYTOMEGALOVIRUS-INFECTED CELLS
A PROTEIN-KINASE HOMOLOG CONTROLS PHOSPHORYLATION OF GANCICLOVIR IN HUMAN CYTOMEGALOVIRUS-INFECTED CELLS
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DOI：
10.1038/358162a0
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发表时间：
1992-07-09
期刊：
影响因子：
64.8
通讯作者：
BIRON, KK
中科院分区：
文献类型：
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作者：
SULLIVAN, V;TALARICO, CL;BIRON, KK
人类巨细胞病毒 (HCMV) 是免疫抑制个体（包括获得性免疫缺陷综合征患者）的主要病原体。核苷类似物更昔洛韦（9-(1,3-二羟基-2-丙氧基甲基)-鸟嘌呤）是少数可用于治疗 HCMV 感染的药物之一，但耐药病毒是临床上日益严重的问题 1，因此迫切需要新药。对更昔洛韦耐药突变体的研究表明，更昔洛韦的选择性作用很大程度上取决于HCMV感染细胞中病毒控制的磷酸化2-5。尚未确定负责的酶。在这里，我们报道了 HCMV 基因 UL97，其预测产物与蛋白激酶、鸟苷酸环化酶和细菌磷酸转移酶 6-8 具有同源区域，控制着 HCMV 感染细胞中更昔洛韦的磷酸化。 UL97 保守区域的四个氨基酸缺失（在环 AMP 依赖性蛋白激酶中参与底物识别 9）会导致更昔洛韦磷酸化受损。讨论了这些结果对抗病毒药物开发和耐药性的影响。
HUMAN cytomegalovirus (HCMV) is a major pathogen in immunosuppressed individuals, including patients with acquired immune deficiency syndrome. The nucleoside analogue ganciclovir (9-(1,3-dihydroxy-2-propoxymethyl)-guanine) is one of the few drugs available to treat HCMV infections, but resistant virus is a growing problem in the clinic 1 and there is a critical need for new drugs. The study of ganciclovir-resistant mutants has indicated that the selective action of ganciclovir depends largely on virus-controlled phosphorylation in HCMV-infected cells 2-5. The enzyme(s) responsible have not been identified. Here we report that the HCMV gene UL97, whose predicted product shares regions of homology with protein kinases, guanylyl cyclase and bacterial phosphotransferases 6-8, controls phosphorylation of ganciclovir in HCMV-infected cells. A four-amino-acid deletion of UL97 in a conserved region, which in cyclic AMP-dependent protein kinase participates in substrate recognition 9, causes impaired ganciclovir phosphorylation. The implications of these results for antiviral drug development and drug resistance are discussed.