Viral and cellular RNA helicases as antiviral targets.
Viral and cellular RNA helicases as antiviral targets.
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DOI：
10.1038/nrd1853
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发表时间：
2005-10
期刊：
影响因子：
--
通讯作者：
Jeang KT
中科院分区：
文献类型：
--
作者：
Kwong AD;Rao BG;Jeang KT
迄今为止，尽管许多病毒感染可以通过疫苗接种成功预防，但我们缺乏对许多重要人类病原体（包括丙型肝炎病毒（HCV）和人类免疫缺陷病毒（HIV））疫苗的有效了解。因此，将需要抗病毒药物来治疗许多病毒性疾病。病毒编码的酶和适合病毒复制的细胞酶可能是抗病毒药物的有用靶点。针对病毒或细胞多肽的药物具有不同的含义。独特病毒功能的抑制剂具有较低的毒性风险，而被病毒使用的细胞酶的抑制剂具有较窄的有效窗口而不产生毒性。所有的病毒似乎都需要解旋酶功能来复制。HCV编码病毒RNA解旋酶，最近的研究结果表明，HIV-1适应其病毒生命周期的细胞RNA解旋酶。这些观察结果提高了小分子解旋酶抑制剂作为抗病毒治疗的一般模式的可能性。解旋酶属于具有保守基序的三个超家族（SF 1、SF 2和SF 3）。保守的基序与保守的解旋酶功能相关。然而，在保守基序之外，解旋酶之间的一级序列和三级结构差异很大。在这方面，可以利用病毒病原体的解旋酶与细胞解旋酶之间的一级序列和三级结构的差异来赋予抗病毒抑制剂特异性。活性解旋酶的构象可以大致分为“开放”和“封闭”复合物。用于鉴定小分子解旋酶抑制剂的策略包括：通过与NTP结合的直接竞争来抑制NTP活性;竞争性地抑制核酸结合;通过阻断结构域2的移动来抑制NTP水解或NDP释放;抑制将NTP水解与核酸的易位和解旋偶联的过程;通过空间阻断解旋酶易位来抑制解旋;以及抑制解旋。其他潜在的抑制机制包括改变解旋酶的物理构象的机制，或破坏解旋酶周转的机制，或抑制解旋酶与其他关键蛋白相互作用的机制。解旋酶抑制剂作为抗病毒药物的概念的临床前证据已经获得用于HSV。这一突破性的发现提供了迄今为止最好的证据，证明有可能开发出选择性的、有效的病毒解旋酶抑制剂作为抗病毒剂。目前正在对具有抗HCV或HIV-1活性的抗解旋酶分子进行研究。尽管近年来抗病毒剂的开发取得了相当大的进展，但仍然迫切需要新的药物来改善现有药物的性质并对抗病毒耐药性问题。解旋酶，无论是病毒和人类，最近出现作为新的目标，用于治疗病毒感染。在这里，我们讨论了这些酶的作用，影响其作为药物靶点的潜力的因素，并以丙型肝炎病毒编码的解旋酶NS 3和HIV-1使用的细胞解旋酶DDX 3为例，在开发抑制其活性的药物方面取得了进展。
To date, although many viral infections can be successfully prevented via vaccination, we lack effective knowledge of vaccines for numerous important human pathogens, including hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Accordingly, antiviral drugs will be needed to treat many viral diseases. Virally encoded enzymes and cellular enzymes adapted for use by viruses for replication might represent useful targets for antiviral drugs. Drugs that target either a viral or cellular polypeptide hold different implications. Inhibitors of unique viral functions have a lower risk of toxicity, whereas inhibitors of cellular enzymes that are used by viruses have a narrower window for efficacy without creating toxicity. All viruses seem to require a helicase function for replication. HCV encodes a viral RNA helicase, and recent findings have shown that HIV-1 adapts a cellular RNA helicase for its viral lifecycle. These observations raise the possibility of small-molecule helicase inhibitors as a general mode of antiviral therapy. Helicases fall into three super-families (SF1, SF2 and SF3) with conserved motifs. The conserved motifs are associated with conserved helicase function. However, outside of the conserved motifs the primary sequences and tertiary structures between helicases are differ greatly. In this regard, differences in primary sequence and tertiary structure between the helicase of a viral pathogen and that of cellular helicases can be exploited to confer specificity to an antiviral inhibitor. The conformation of an active helicase can be broadly divided into an 'open' and a 'closed' complex. Strategies for identifying small-molecule helicase inhibitors include: inhibiting NTPase activity by direct competition with NTP binding; competitively inhibit nucleic-acid binding; inhibiting NTP hydrolysis or NDP release by blocking the movement of domain 2; inhibiting the process that couples NTP hydrolysis to translocation and unwinding of nucleic acid; inhibiting unwinding by sterically blocking helicase translocation; and inhibiting unwinding. Other potential inhibitory mechanisms include those that change the physical conformation of the helicase, or those that disrupt helicase turnover, or those that inhibit helicase interaction with other crucial proteins. Preclinical proof of concept for helicase inhibitors as antiviral agents has been obtained for HSV. This breakthrough finding provides the best evidence to date that it is possible to develop selective, potent inhibitors of a viral helicase as antiviral agents. Searches are ongoing for antihelicase molecules that have activity against HCV or HIV-1. Although there has been considerable progress in the development of antiviral agents in recent years, there is still a pressing need for new drugs both to improve on the properties of existing agents and to combat the problem of viral resistance. Helicases, both viral and human, have recently emerged as novel targets for the treatment of viral infections. Here, we discuss the role of these enzymes, factors affecting their potential as drug targets and progress in the development of agents that inhibit their activity using the hepatitis C virus-encoded helicase NS3 and the cellular helicase DDX3 adopted for use by HIV-1 as examples.
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影响因子：
4.9
作者：
Betz, UAK;Fischer, R;Rübsamen-Waigmann, H
通讯作者：
Rübsamen-Waigmann, H
影响因子：
5.4
作者：
Hong, Z;Ferrari, E;Kwong, AD
通讯作者：
Kwong, AD
DOI：
10.1038/nrmicro975
发表时间：
2004-09
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
De Clercq E
通讯作者：
De Clercq E
影响因子：
5.4
作者：
Bressanelli, S;Tomei, L;De Francesco, R
通讯作者：
De Francesco, R
影响因子：
6.8
作者：
GORBALENYA, AE;KOONIN, EV
通讯作者：
KOONIN, EV