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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Potent and Selective Inhibition of Human Cytomegalovirus Replication by 1263W94, a Benzimidazole L-Riboside with a Unique Mode of Action.
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Potent and Selective Inhibition of Human Cytomegalovirus Replication by 1263W94, a Benzimidazole L-Riboside with a Unique Mode of Action.

机译：对人巨细胞病毒复制的有力和选择性抑制作用是1263W94，一种具有独特作用方式的苯并咪唑L-核苷。

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摘要

Benzimidazole nucleosides have been shown to be potent inhibitors of human cytomegalovirus (HCMV) replication in vitro. As part of the exploration of structure-activity relationships within this series, we synthesized the 2-isopropylamino derivative (3322W93) of 1H-beta-D-ribofuranoside-2-bromo-5,6-dichlorobenzimidazole (BDCRB) and the biologically unnatural L-sugars corresponding to both compounds. One of the L derivatives, 1H-beta-L-ribofuranoside-2-isopropylamino-5,6-dichlorobenzimidazole (1263W94), showed significant antiviral potency in vitro against both laboratory HCMV strains and clinical HCMV isolates, including those resistant to ganciclovir (GCV), foscarnet, and BDCRB. 1263W94 inhibited viral replication in a dose-dependent manner, with a mean 50% inhibitory concentration (IC(50)) of 0.12 +/- 0.01 microM compared to a mean IC(50) for GCV of 0.53 +/- 0.04 microM, as measured by a multicycle DNA hybridization assay. In a single replication cycle, 1263W94 treatment reduced viral DNA synthesis, as well as overall virus yield. HCMV mutants resistant to 1263W94 were isolated, establishing that the target of 1263W94 was a viral gene product. The resistance mutation was mapped to the UL97 open reading frame. The pUL97 protein kinase was strongly inhibited by 1263W94, with 50% inhibition occurring at 3 nM. Although HCMV DNA synthesis was inhibited by 1263W94, the inhibition was not mediated by the inhibition of viral DNA polymerase. The parent benzimidazole D-riboside BDCRB inhibits viral DNA maturation and processing, whereas 1263W94 does not. The mechanism of the antiviral effect of L-riboside 1263W94 is thus distinct from those of GCV and of BDCRB. In summary, 1263W94 inhibits viral replication by a novel mechanism that is not yet completely understood.
机译：苯并咪唑核苷已被证明是体外人巨细胞病毒（HCMV）复制的有效抑制剂。作为探索该系列结构与活性关系的一部分，我们合成了1H-β-D-核呋喃糖苷-2-溴-5,6-二氯苯并咪唑（BDCRB）的2-异丙基氨基衍生物（3322W93）和生物学上不自然的L -对应于两种化合物的糖。 L衍生物之一1H-β-L-呋喃呋喃糖苷-2-异丙氨基-5,6-二氯苯并咪唑（1263W94）在体外对实验室HCMV菌株和临床HCMV分离株均表现出显着的抗病毒效力，包括对更昔洛韦（GCV）耐药的菌株），foscarnet和BDCRB。 1263W94以剂量依赖的方式抑制病毒复制，平均50％抑制浓度（IC（50））为0.12 +/- 0.01 microM，而GCV的平均IC（50）为0.53 +/- 0.04 microM，通过多周期DNA杂交测定法测定。在一个复制周期中，1263W94处理降低了病毒DNA的合成以及总的病毒产量。分离出了对1263W94具有抗性的HCMV突变体，确定了1263W94的靶标是病毒基因产物。抗性突变被映射到UL97开放阅读框。 pUL97蛋白激酶被1263W94强烈抑制，在3 nM时发生50％抑制。尽管HCMV DNA的合成受到1263W94的抑制，但该抑制作用并未受到病毒DNA聚合酶抑制作用的介导。亲本苯并咪唑D-核糖BDCRB抑制病毒DNA的成熟和加工，而1263W94则不。因此，L-核糖苷1263W94的抗病毒作用机制与GCV和BDCRB的机制不同。总之，1263W94通过一种尚不完全了解的新机制抑制病毒复制。

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