Departments of Pediatrics, Medical College of Virginia Campus of Virginia Commonwealth University, 1101 E. Marshall Street, Richmond, VA 23298-0163, USA.
Departments of Medicine, Medical College of Virginia Campus of Virginia Commonwealth University, 1101 E. Marshall Street, Richmond, VA 23298-0163, USA.
Antiviral Res. 2018 Jun;154:44-50. doi: 10.1016/j.antiviral.2018.04.006. Epub 2018 Apr 9.
Herpesvirus DNA packaging is an essential step in virion morphogenesis and an important target for antiviral development. The halogenated benzimidazole 2-bromo-5,6-dichloro-1-β-d-ribofuranosyl-1H-benzimidazole (BDCRB) was the first compound found to selectively disrupt DNA packaging. It has activity against human cytomegalovirus as well as guinea pig cytomegalovirus. The latter provides a useful small animal model for congenital cytomegalovirus infection. To better understand the mechanism by which BDCRB acts, a guinea pig cytomegalovirus resistant to BDCRB was derived and characterized. An L406P substitution occurred within GP89, a subunit of the complex that cleaves and packages DNA, but transfer of this mutation to an otherwise wild type genetic background did not confer significant BDCRB resistance. The resistant virus also had a 13.4-kb deletion that also appeared to be unrelated to BDCRB-resistance as a virus with a similar spontaneous deletion was sensitive to BDCRB. Lastly, the BDCRB-resistant virus exhibited a dramatic increase in the number of reiterated terminal repeats at both genomic termini. The mechanism that underlies this change in genome structure is not known but may relate to the duplication of terminal repeats that is associated with DNA cleavage and packaging. A model is presented in which BDCRB impairs the ability of terminase to recognize cleavage site sequences, but repeat arrays overcome this impairment by presenting terminase with multiple opportunities to recognize the correct cleavage site sequences that lie within the repeats. Further elucidation of this phenomenon should prove valuable for understanding the molecular basis of herpesvirus DNA maturation and the mechanism of action of this class of drugs.
疱疹病毒 DNA 包装是病毒形态发生的一个必要步骤，也是抗病毒药物开发的一个重要靶点。卤代苯并咪唑 2-溴-5,6-二氯-1-β-D-呋喃核糖基-1H-苯并咪唑（BDCRB）是第一个被发现可选择性破坏 DNA 包装的化合物。它对人巨细胞病毒和豚鼠巨细胞病毒均有活性。后者为先天性巨细胞病毒感染提供了一个有用的小动物模型。为了更好地了解 BDCRB 的作用机制，构建并鉴定了对 BDCRB 具有抗性的豚鼠巨细胞病毒。在切割和包装 DNA 的复合物的一个亚基 GP89 中发生了 L406P 取代，但将该突变转移到其他野生型遗传背景中并没有赋予其对 BDCRB 的显著抗性。该抗性病毒还存在 13.4kb 的缺失，这似乎与 BDCRB 抗性无关，因为具有类似自发缺失的病毒对 BDCRB 敏感。最后，BDCRB 抗性病毒在基因组两端的重复末端重复序列数量上显著增加。这种基因组结构变化的机制尚不清楚，但可能与与 DNA 切割和包装相关的末端重复序列的复制有关。提出了一种模型，其中 BDCRB 损害了终止酶识别切割位点序列的能力，但重复序列通过为终止酶提供多次识别位于重复序列内的正确切割位点序列的机会来克服这种损害。进一步阐明这一现象对于理解疱疹病毒 DNA 成熟的分子基础以及该类药物的作用机制应该是有价值的。
