Dargan D J, Subak-Sharpe J H
J Antimicrob Chemother. 1986 Oct;18 Suppl B:185-200. doi: 10.1093/jac/18.supplement_b.185.
Dose-response experiments show that the presence of 300 microM cicloxolone sodium (CCX) or 500 microM carbenoxolone sodium (CBX) during the HSV replication cycle reduced the infectious virus yield by 10,000- to 100,000-fold: CCX is the more potent anti-herpes agent. HSV-2 replication was consistently more severely restricted by either drug than was that of HSV-1. The ED50 values obtained for either drug against HSV-1 or HSV-2 correlate well with data from dose-response curves. CCX, and to a lesser extent CBX, can be cytotoxic but the degree of cytotoxicity varies between cell lines and is also affected by the physiological state of the cells. Triterpenoid drugs exhibit some activity against virus particles in suspension but the effect is small and contributes little to the overall antiviral effect. The drugs appear to be active throughout the replication cycle. In contrast to all other anti-herpesvirus agents in clinical use the triterpenoid compounds do not appear to act directly to block virus DNA synthesis. HSV mutants resistant to ACG and PAA, or lacking a thymidine kinase gene, appear as sensitive as wild-type virus to CCX inhibition. HSV growth in the presence of the drugs resulted in a lower number of assembled virus particles but reduced to a much greater extent the infectious virus yield: thus the progeny virus quality is greatly diminished. Thermolability of progeny virus correlated well with this diminution of quality in increasing CCX concentration. SDS PAGE analysis of the structural proteins of virus particles made in cells treated with 300 microM CCX revealed numerous differences in the relative intensities of protein bands, which is in keeping with the changed quality of the drug-produced virus. SDS PAGE analysis of the polypeptides induced in drug treated infected cells revealed two effects; some polypeptides were synthesised in reduced amounts and the nuclear/cytoplasmic distribution of certain proteins was affected. Post-translational processing by glycosylation and sulphation of both cellular and HSV induced proteins was strongly inhibited by the triterpenoid drugs, while phosphorylation of only a few polypeptides appeared to be affected.
剂量反应实验表明，在单纯疱疹病毒（HSV）复制周期中存在300微摩尔环氯索钠（CCX）或500微摩尔甘珀酸钠（CBX）时，传染性病毒产量降低了10000至100000倍：CCX是更有效的抗疱疹药物。与HSV-1相比，HSV-2的复制始终受到这两种药物更严重的限制。两种药物对HSV-1或HSV-2的半数有效剂量（ED50）值与剂量反应曲线的数据相关性良好。CCX以及程度较轻的CBX可能具有细胞毒性，但细胞毒性程度在不同细胞系之间有所不同，并且也受细胞生理状态的影响。三萜类药物对悬浮中的病毒颗粒表现出一定活性，但效果较小，对整体抗病毒效果贡献不大。这些药物在整个复制周期似乎都有活性。与临床使用的所有其他抗疱疹病毒药物不同，三萜类化合物似乎并非直接作用于阻断病毒DNA合成。对阿昔洛韦（ACG）和磷甲酸（PAA）耐药或缺乏胸苷激酶基因的HSV突变体，对CCX抑制的敏感性似乎与野生型病毒相同。在药物存在下HSV生长导致组装的病毒颗粒数量减少，但传染性病毒产量降低的程度更大：因此子代病毒质量大大降低。子代病毒的热稳定性与随着CCX浓度增加质量的降低密切相关。对用300微摩尔CCX处理的细胞中产生的病毒颗粒的结构蛋白进行十二烷基硫酸钠聚丙烯酰胺凝胶电泳（SDS PAGE）分析，发现蛋白条带的相对强度存在许多差异，这与药物产生的病毒质量变化一致。对药物处理的感染细胞中诱导的多肽进行SDS PAGE分析揭示了两种效应；一些多肽合成量减少，某些蛋白质的核/细胞质分布受到影响。三萜类药物强烈抑制细胞和HSV诱导蛋白通过糖基化和硫酸化进行的翻译后加工，而只有少数多肽的磷酸化似乎受到影响。
