Geldanamycin, a ligand of heat shock protein 90, inhibits the replication of herpes simplex virus type 1 in vitro
Geldanamycin, a ligand of heat shock protein 90, inhibits the replication of herpes simplex virus type 1 in vitro
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DOI：
10.1128/aac.48.3.867-872.2004
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发表时间：
2004-03-01
影响因子：
4.9
通讯作者：
Jiang, JD
中科院分区：
文献类型：
--
作者：
Li, YH;Tao, PZ;Jiang, JD
格尔德霉素（GA）是一种针对热休克蛋白90（Hsp 90）ADP/ATP结合位点的抗生素。在筛选抗单纯疱疹病毒1型（HSV-1）的候选人，我们发现GA对HSV-1的活性。HSV-1体外复制被GA显著抑制，50%抑制浓度为0.093 μ M，与350 μ M的未处理对照相比，GA抑制细胞生长50%的浓度。GA的治疗指数超过3，700（与阿昔洛韦的结果相当）。GA不抑制HSV-1胸苷激酶。感染HSV-1的细胞表现出细胞周期停滞在G（1）/S转换;然而，用GA处理导致细胞周期分布模式与未处理的细胞相同，表明GA处理恢复HSV-1感染细胞的细胞生长。因此，在用GA处理的HSV-1（+）细胞中，HSV-1 DNA合成受到抑制。GA的抗病毒机制与Hsp 90失活和细胞周期恢复有关，表明GA具有广谱抗病毒活性。事实上，GA在体外表现出对其他病毒的活性，包括严重急性呼吸综合征冠状病毒。由于GA通过HSV-1药物中独特的细胞机制抑制HSV-1，我们认为它是HSV-1的新候选药物。
Geldanamycin (GA) is an antibiotic targeting the ADP/ATP binding site of heat shock protein 90 (Hsp90). In screening for anti-herpes simplex virus type 1 (HSV-1) candidates, we found GA active against HSV-1. HSV-1 replication in vitro was significantly inhibited by GA with an 50% inhibitory concentration of 0.093 muM and a concentration that inhibited cellular growth 50% in comparison with the results seen with untreated controls of 350 muM. The therapeutic index of GA was over 3,700 (comparable to the results seen with acyclovir). GA did not inhibit HSV-1 thymidine kinase. Cells infected with HSV-1 demonstrated cell cycle arrest at the G(1)/S transition; however, treatment with GA resulted in a cell cycle distribution pattern identical to that of untreated cells, indicating a restoration of cell growth in HSV-1-infected cells by GA treatment. Accordingly, HSV-1 DNA synthesis was suppressed in HSV-1(+) cells treated with GA. The antiviral mechanism of GA appears to be associated with Hsp90 inactivation and cell cycle restoration, which indicates that GA exhibits broad-spectrum antiviral activity. Indeed, GA exhibited activities in vitro against other viruses, including severe acute respiratory syndrome coronavirus. Since GA inhibits HSV-1 through a cellular mechanism unique among HSV-1 agents, we consider it a new candidate agent for HSV-1.