Synthesis and biological evaluation of heat-shock protein 90 inhibitors: geldanamycin derivatives with broad antiviral activities
Synthesis and biological evaluation of heat-shock protein 90 inhibitors: geldanamycin derivatives with broad antiviral activities
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DOI：
10.3851/imp1631
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发表时间：
2010-01-01
影响因子：
--
通讯作者：
Li, Zhuo-Rong
中科院分区：
文献类型：
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作者：
Li, Yan-Ping;Shan, Guang-Zhi;Li, Zhuo-Rong
背景：先前的研究表明格尔德霉素（GA）在体外抑制几种病毒的复制。方法：合成17-氨基-17-去甲氧基格尔德霉素衍生物，并对其抗疱疹病毒、肝炎病毒、逆转录病毒和小核糖核酸病毒等8种病毒株的活性进行筛选。与母体化合物GA相比，大多数测试化合物显示出对病毒的抑制活性，并且显示出降低的体外细胞毒性。体内功效评价结果显示，口服给药后，化合物6显著抑制了雏鸭血清中的雏鸭乙型肝炎B病毒DNA复制。治疗终止后未发生病毒反弹。修改后的GA衍生物也表现出半数致死剂量值高于母体GA在小鼠腹腔内治疗的研究compounds.Conclusions：靶向热休克蛋白90可能是一种新的抗病毒方法，是不容易发展耐药性。17-氨基-17-去甲氧基格尔德霉素衍生物可能是具有潜在抗病毒活性的新型药物。
Background: Previous studies have suggested that geldanamycin (GA) inhibits the replication of several viruses in vitro. Here, we aimed to synthesize and evaluate the antiviral activity of 17-amino-17-demethoxygeldanamycin derivatives.Methods: A series of 17-substituted and 17-, 19-disubstituted GA derivatives were screened for antiviral activities against eight different viral strains, including herpesvirus, hepatitis virus, retrovirus and picornavirus.Results: Most of the tested compounds showed inhibitory activity against the viruses and showed reduced cytotoxicity in vitro as compared with the parent compound GA. In vivo efficacy evaluation results showed that compound 6 noticeably inhibited duckling hepatitis B virus DNA replication in duckling serum after oral administration. Viral rebound did not occur after termination of the treatment. The modified GA derivatives also showed median lethal dose values that were higher than that of the parent GA in mice intraperitoneally treated with the study compounds.Conclusions: Targeting heat-shock protein 90 could be a new antiviral approach that is not prone to the development of drug resistance. The 17-amino-17-demethoxygeldanamycin derivatives could be novel agents with potential antiviral activity.