University of Alabama at Birmingham, Department of Pediatrics, 128 Children's Harbor Building, 1600 6th Avenue South, Birmingham, AL 35233-1711, USA.
Antimicrob Agents Chemother. 2011 Oct;55(10):4682-91. doi: 10.1128/AAC.00571-11. Epub 2011 Jul 25.
Cyclopropavir (CPV) is active against human cytomegalovirus (CMV), as well as both variants of human herpesvirus 6 and human herpesvirus 8. The mechanism of action of CPV against CMV is similar to that of ganciclovir (GCV) in that it is phosphorylated initially by the CMV UL97 kinase, resulting in inhibition of viral DNA synthesis. Resistance to CPV maps to the UL97 kinase but is associated primarily with H520Q mutations and thus retains good antiviral activity against most GCV-resistant isolates. An examination of CMV-infected cultures treated with CPV revealed unusual cell morphology typically associated with the absence of UL97 kinase activity. A surrogate assay for UL97 kinase activity confirmed that CPV inhibited the activity of this enzyme and that its action was similar to the inhibition seen with maribavir (MBV) in this assay. Combination studies using real-time PCR indicated that, like MBV, CPV also antagonized the efficacy of GCV and were consistent with the observed inhibition of the UL97 kinase. Deep sequencing of CPV-resistant laboratory isolates identified a frameshift mutation in UL27, presumably to compensate for a loss of UL97 enzymatic activity. We conclude that the mechanism of action of CPV against CMV is complex and involves both the inhibition of DNA synthesis and the inhibition of the normal activity of the UL97 kinase.
环丙沙星（CPV）对人巨细胞病毒（CMV）以及人疱疹病毒 6 型和人疱疹病毒 8 型的两种变体均具有活性。CPV 对 CMV 的作用机制与更昔洛韦（GCV）相似，即最初被 CMV UL97 激酶磷酸化，从而抑制病毒 DNA 合成。CPV 耐药性与 UL97 激酶有关，但主要与 H520Q 突变相关，因此对大多数 GCV 耐药株仍具有良好的抗病毒活性。对 CPV 处理的 CMV 感染培养物的检查显示出异常的细胞形态，通常与 UL97 激酶活性缺失有关。对 UL97 激酶活性的替代测定证实 CPV 抑制了该酶的活性，其作用与该测定中 MBV 的抑制作用相似。使用实时 PCR 的联合研究表明，CPV 与 MBV 一样，也拮抗 GCV 的疗效，与观察到的 UL97 激酶抑制一致。对 CPV 耐药的实验室分离株进行深度测序发现 UL27 发生移码突变，可能是为了弥补 UL97 酶活性的丧失。我们得出结论，CPV 对 CMV 的作用机制复杂，涉及 DNA 合成的抑制和 UL97 激酶正常活性的抑制。
