Targeting human papillomavirus genome replication for antiviral drug discovery.
Targeting human papillomavirus genome replication for antiviral drug discovery.
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DOI：
10.3851/imp2612
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发表时间：
2013
影响因子：
1.2
通讯作者：
Melendy T
中科院分区：
文献类型：
--
作者：
Archambault J;Melendy T
人类乳头瘤病毒(HPV)感染是人类的一个主要健康问题；它们是复发的良性疣和几种肛门生殖道和头颈部癌症的原因。虽然有两种预防性HPV疫苗，如果普遍使用，可以预防多达三分之二的HPV诱导的癌症，以及几种用于局部治疗感染的细胞毒性和免疫调节剂，但目前我们的治疗剂库中没有HPV抗病毒药物。本综述考察了过去和正在进行的HPV抗病毒药物开发的研究现状，主要集中在针对病毒基因组复制的方法。唯一的HPV酶，E1，是一种DNA解旋酶，它与细胞DNA复制机制相连，复制HPV基因组。到目前为止，寻找E1的小分子抑制剂作为抗病毒药物的成功有限。缺乏其他病毒酶意味着抗病毒药物的寻找在很大程度上转向了蛋白质-蛋白质相互作用的调节。在识别针对HPV蛋白之间相互作用的小分子抑制剂方面已经取得了一些成功，但仅对一小部分病毒类型具有活性。正如这篇综述中指出的那样，人们认为靶向E1与细胞复制蛋白的相互作用可能提供对多种HPV类型具有更广泛活性的抑制剂。在这里，我们概述了HPV DNA复制的步骤，并讨论了那些似乎为抗HPV治疗药物的发展提供了最有利的靶点。
Human papillomavirus (HPV) infections are a major human health problem; they are the cause of recurrent benign warts and of several cancers of the anogenital tract and head and neck region. Although there are two prophylactic HPV vaccines that could, if used universally, prevent as many as two-thirds of HPV-induced cancers, as well as several cytotoxic and immunomodulatory agents for localized treatment of infections, there are currently no HPV antiviral drugs in our arsenal of therapeutic agents. This review examines the status of past and ongoing research into the development of HPV antivirals, focused primarily upon approaches targeting the replication of the viral genome. The only HPV enzyme, E1, is a DNA helicase that interfaces with the cellular DNA replication machinery to replicate the HPV genome. To date, searches for small molecule inhibitors of E1 for use as antivirals have met with limited success. The lack of other viral enzymes has meant that the search for antivirals has shifted to a large degree to the modulation of protein–protein interactions. There has been some success in identifying small molecule inhibitors targeting interactions between HPV proteins but with activity against a small subset of viral types only. As noted in this review, it is thought that targeting E1 interactions with cellular replication proteins may provide inhibitors with broader activity against multiple HPV types. Herein, we outline the steps in HPV DNA replication and discuss those that appear to provide the most advantageous targets for the development of anti-HPV therapeutics.