Early inhibitors of human cytomegalovirus: state-of-art and therapeutic perspectives.
Early inhibitors of human cytomegalovirus: state-of-art and therapeutic perspectives.
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DOI：
10.1016/j.pharmthera.2011.04.007
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发表时间：
2011-09
影响因子：
13.5
通讯作者：
Loregian A
中科院分区：
文献类型：
--
作者：
Mercorelli B;Lembo D;Palù G;Loregian A
人巨细胞病毒（HCMV）感染与免疫功能低下个体（主要是移植受者和AIDS患者）的严重发病率和死亡率相关，并且是新生儿先天性畸形的最常见原因。迄今为止，很少有药物获得许可用于治疗HCMV感染，其中大多数药物针对病毒DNA聚合酶，并且存在许多缺点，包括长期毒性、效力低和生物利用度差。此外，抗药性病毒株的出现正在成为疾病管理的一个日益严重的问题。最后，目前没有一种抗HCMV药物被批准用于治疗先天性感染。由于所有这些原因，仍然强烈需要具有新的作用机制的新的抗HCMV药物。病毒复制周期的第一个事件，包括附着、进入、立即早期基因表达和立即早期功能，特别是立即早期2蛋白，代表了开发新型抗病毒化合物的有吸引力的靶点。这种抑制剂不仅可以阻断病毒立即早期蛋白的表达，这在HCMV感染的发病机制中起关键作用，而且还可以阻断宿主免疫调节和病毒感染的第一个事件引起的细胞生理学变化。本文综述了HCMV复制的初始阶段，它们作为潜在的新型抗病毒靶点的验证，以及阻断这种过程的化合物的开发的现有知识。
Human cytomegalovirus (HCMV) infection is associated with severe morbidity and mortality in immunocompromised individuals, mainly transplant recipients and AIDS patients, and is the most frequent cause of congenital malformations in newborn children. To date, few drugs are licensed for the treatment of HCMV infections, most of which target the viral DNA polymerase and suffer from many drawbacks, including long-term toxicity, low potency, and poor bioavailability. In addition, the emergence of drug-resistant viral strains is becoming an increasing problem for disease management. Finally, none of the current anti-HCMV drugs have been approved for the treatment of congenital infections. For all these reasons, there is still a strong need for new anti-HCMV drugs with novel mechanisms of action. The first events of the virus replication cycle, including attachment, entry, immediate-early gene expression, and immediate-early functions—in particular that of Immediate-Early 2 protein—represent attractive targets for the development of novel antiviral compounds. Such inhibitors would block not only the expression of viral immediate-early proteins, which play a key role in the pathogenesis of HCMV infection, but also the host immunomodulation and the changes to cell physiology induced by the first events of virus infection. This review describes the current knowledge on the initial phases of HCMV replication, their validation as potential novel antiviral targets, and the development of compounds that block such processes.
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