Interactions among antiviral drugs acting late in the replication cycle of human cytomegalovirus
Interactions among antiviral drugs acting late in the replication cycle of human cytomegalovirus
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DOI：
10.1016/s0166-3542(02)00094-3
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发表时间：
2002-10-01
影响因子：
7.6
通讯作者：
Drach, JC
中科院分区：
文献类型：
--
作者：
Evers, DL;Komazin, G;Drach, JC
本研究描述了人巨细胞病毒（HCMV）DNA合成和DNA加工抑制剂的交叉耐药程度和相互作用。对苯并咪唑D-核糖核苷病毒DNA加工抑制剂TCRB和BDCRB耐药的HCMV分离株对病毒DNA加工的非核苷抑制剂BAY 38-4766敏感。这表明这两种药物类型与病毒DNA切割和包装所需的HCMV基因UL 56和UL 89的产物具有不同的相互作用。这些病毒分离株也对更昔洛韦（GCV）敏感，但对L-苯并咪唑核糖核苷病毒DNA合成抑制剂1263 W 94略耐药。对1263 W 94耐药的病毒对BDCRB、GCV和BAY 38-4766保持敏感。在测量HCMV复制抑制的细胞培养试验中检查药物相互作用，发现BDCRB与1263 W 94联合用药以及1263 W 94与西多福韦（CDV）和膦甲酸（PFA）联合用药具有强协同作用，但与GCV无协同作用。GCV与CDV和PFA的组合也具有协同作用。GCV与1263 W 94联合用药显示出相加的抗病毒相互作用，而BAY 38-4766与GCV联合用药显示出拮抗作用。BDCRB与BAY 38-4766的相互作用显示协同和拮抗的混合模式。在GCV和PFA或CDV之间观察到的抗病毒协同作用用于验证这些药物的临床联合治疗。BAY 38-4766与GCV的拮抗作用表明这两种药物不太可能用于联合治疗。值得注意的是，1263 W 94与PFA或CDV联合使用时显示出比GCV更大的协同作用，表明这种苯并咪唑L-核苷在此类联合治疗中具有一定的前景。(C)2002 Elsevier Science B. V.保留所有权利。
This study describes the extent of cross-resistance and interactions for selected inhibitors of human cytomegalovirus (HCMV) DNA synthesis and DNA processing. HCMV isolates resistant to the benzimidazole D-ribonucleoside viral DNA processing inhibitors TCRB and BDCRB were sensitive to BAY 38-4766, a non-nucleoside inhibitor of viral DNA processing. This indicates that these two drug types have distinct interactions with the products of HCMV genes UL56 and UL89 required for viral DNA cleavage and packaging. These virus isolates also were sensitive to ganciclovir (GCV) but slightly resistant to the L-benzimidazole ribonucleoside viral DNA synthesis inhibitor 1263W94. Virus resistant to 1263W94 remained sensitive to BDCRB, GCV, and BAY 38-4766. Examination of drug-drug interactions in cell culture assays measuring inhibition of HCMV replication revealed strong synergism for the combination of BDCRB with 1263W94, and for combinations of 1263W94 with cidofovir (CDV) and foscarnet (PFA), but not with GCV. Combinations of GCV with CDV and PFA were synergistic as well. The combination of GCV with 1263W94 showed additive antiviral interactions, whereas, a combination of BAY 38-4766 with GCV showed antagonism. Interaction of BDCRB with BAY 38-4766 showed a mixed pattern of synergy and antagonism. The antiviral synergy observed between GCV and PFA or CDV serves to validate clinical combination therapies for these drugs. Antagonism seen for BAY 38-4766 with GCV indicates that these two drugs are unlikely to be useful for combination therapies. Notably, 1263W94 demonstrated greater synergy in combination with PFA or CDV than did GCV, suggesting some promise for this benzimidazole L-riboside in such combination therapies. (C) 2002 Elsevier Science B.V. All rights reserved.