Inhibition of human cytomegalovirus signaling and replication by the immunosuppressant FK778
Inhibition of human cytomegalovirus signaling and replication by the immunosuppressant FK778
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DOI：
10.1016/j.antiviral.2004.03.007
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发表时间：
2005-01-01
影响因子：
7.6
通讯作者：
Huang, ES
中科院分区：
文献类型：
--
作者：
Evers, DL;Wang, X;Huang, ES
FK778（Fujisawa Healthcare Inc.）是一种免疫抑制剂，其结构类似于来氟米特（Aventis Pharmaceuticals）的活性代谢物 A771726，但临床相关的血清半衰期较短。来氟米特。一种对接受同种异体移植的患者具有耐受性且有效的免疫抑制剂，据报道对 HCMV 和 HSV-1 具有活性。在这里，我们报道 FK778 是一种强效且有效的 HCMV 抑制剂，其抗病毒作用模式似乎反映了其他地方描述的导致其免疫抑制特性的生化机制：抑制蛋白质酪氨酸磷酸化和抑制细胞从头嘧啶生物合成。 FK778 部分抑制了 HCMV 介导的 EGF 受体/磷脂酰肌醇 3 激酶 (PI3-K) 通路以及 Sp1 和 NF-kappaB 的初始激活。 HCMV 诱导 PI3-K、Sp1 和 NF-kappaB 的第二层（阶段）对 FK778 更敏感。用 FK778 处理 HCMV 感染的细胞可在感染后约 12-24 小时阻止 HCMV 蛋白的出现，并抑制病毒 DNA 合成。在我们的检测中，来氟米特还降低了 HCMV DNA 水平。 FK778 的抗病毒活性在细胞培养物中通过尿苷处理而逆转，这与二氢乳清酸脱氢酶 (DHODH) 的特异性抑制一致，二氢乳清酸脱氢酶是嘧啶从头生物合成中所需的酶。该报告证实了单一药物治疗实现免疫抑制和抑制机会性疱疹病毒感染的临床可能性。我们的结果与来氟米特作为 HCMV 细胞质衣壳形成抑制剂的描述不同。此外，这项研究表明 DHODH 可能是一种有效的细胞抗病毒靶点。 (C) 2004 Elsevier B.V. 保留所有权利。
FK778 (Fujisawa Healthcare Inc.) is an immunosuppressant structurally similar to A771726, the active metabolite of leflunomide(Aventis Pharmaceuticals), but with a clinically relevant shorter serum half-life. Leflunomide. a tolerated and efficacious immunosuppressive agent in patients receiving allograft transplantations, was reported to be active against HCMV and HSV-1. Here we report that FK778 is a potent and effective inhibitor of HCMV, and that its mode of antiviral action appears to mirror the biochemical mechanisms elsewhere described to be responsible for its immunosuppressive properties: inhibition of protein tyrosine phosphorylation and inhibition of cellular de novo pyrimidine biosynthesis. Initial HCMV-mediated activation of the EGF receptor/phosphatidylinositol 3-kinase (PI3-K) pathways and Sp1 and NF-kappaB were partially inhibited by FK778. The second tier (phase) of PI3-K, Sp1, and NF-kappaB induction by HCMV was more sensitive to FK778. Treatment of HCMV-infected cells with FK778 prevented the appearance of HCMV proteins some 12-24 h post infection, and inhibited viral DNA synthesis. In our assays, leflunomide also reduced HCMV DNA levels. The antiviral activity of FK778 was reversed in cell culture by treatment with uridine, consistent with specific inhibition of dihydroorotate dehydrogenase (DHODH), a required enzyme in the de novo biosynthesis of pyrimidines. This report substantiates the clinical possibility of a single drug treatment to achieve immunosuppression and inhibit opportunistic herpesvirus infections. Our results differ from descriptions of leflunomide acting as an inhibitor of HCMV cytoplasmic capsid formation. Additionally, this study indicates that DHODH may be an effective cellular antiviral target. (C) 2004 Elsevier B.V. All rights reserved.