Nucleocapsid Protein: A Desirable Target for Future Therapies Against HIV-1.
Nucleocapsid Protein: A Desirable Target for Future Therapies Against HIV-1.
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DOI：
10.1007/82_2015_433
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发表时间：
2015
影响因子：
--
通讯作者：
Mély Y
中科院分区：
文献类型：
--
作者：
Mori M;Kovalenko L;Lyonnais S;Antaki D;Torbett BE;Botta M;Mirambeau G;Mély Y
目前可用的抗HIV-1治疗药物对感染患者非常有益。然而，由于HIV-1的快速变异能力，临床上会出现失败。克服耐药性的一种方法是靶向HIV-1蛋白，这些蛋白在系统发育上相距遥远的病毒株中高度保守，目前没有被现有的治疗方法靶向。在这方面，核衣壳蛋白(NC)是一种锌指蛋白，特别吸引人，因为它高度保守，主要通过与核酸相互作用在病毒复制中发挥核心作用。这种蛋白质的点突变导致非传染性病毒的事实，以及无法选择对第一代抗NC药物具有耐药性的病毒，说明了将NC作为可行的药物靶点的令人信服的理由。在我们的综述中，我们讨论了NC最相关的性质和功能，以及靶向NC的小分子的最新进展。锌喷射器具有很强的抗病毒活性，但由于缺乏特异性而被赋予治疗指数低的毒性。目前，它们主要被研究用于局部杀微生物剂。通过使用非共价NC抑制剂(NCIS)靶向锌指顶部的疏水平台或NC的关键核酸伙伴，可以实现更高的特异性。在过去的几年里，开发了创新的方法来识别NCIS。尽管已鉴定的NCIS的抗病毒活性仍有待提高，但这些化合物有力地支持了NC的药效性，为未来基于结构的设计和高效NCIS的优化铺平了道路。
The currently available anti-HIV-1 therapeutics is highly beneficial to infected patients. However, clinical failures occur as a result of the ability of HIV-1 to rapidly mutate. One approach to overcome drug resistance is to target HIV-1 proteins that are highly conserved among phylogenetically distant viral strains and currently not targeted by available therapies. In this respect, the nucleocapsid (NC) protein, a zinc finger protein, is particularly attractive, as it is highly conserved and plays a central role in virus replication, mainly by interacting with nucleic acids. The compelling rationale for considering NC as a viable drug target is illustrated by the fact that point mutants of this protein lead to noninfectious viruses and by the inability to select viruses resistant to a first generation of anti-NC drugs. In our review, we discuss the most relevant properties and functions of NC, as well as recent developments of small molecules targeting NC. Zinc ejectors show strong antiviral activity, but are endowed with a low therapeutic index due to their lack of specificity, which has resulted in toxicity. Currently, they are mainly being investigated for use as topical microbicides. Greater specificity may be achieved by using non-covalent NC inhibitors (NCIs) targeting the hydrophobic platform at the top of the zinc fingers or key nucleic acid partners of NC. Within the last few years, innovative methodologies have been developed to identify NCIs. Though the antiviral activity of the identified NCIs needs still to be improved, these compounds strongly support the druggability of NC and pave the way for future structure-based design and optimization of efficient NCIs.
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影响因子：
3.4
作者：
Bombarda, Elisa;Grell, Ernst;Mely, Yves
通讯作者：
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影响因子：
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Bazzi A;Zargarian L;Chaminade F;De Rocquigny H;René B;Mély Y;Fossé P;Mauffret O
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3.3
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影响因子：
5.6
作者：
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通讯作者：
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影响因子：
2.9
作者：
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通讯作者：
Mély, Y