Curing a viral infection by targeting the host: the example of cyclophilin inhibitors.
Curing a viral infection by targeting the host: the example of cyclophilin inhibitors.
复制标题
DOI：
10.1016/j.antiviral.2013.03.020
复制
发表时间：
2013-07
影响因子：
7.6
通讯作者：
Gallay, Philippe
中科院分区：
文献类型：
--
作者：
Lin, Kai;Gallay, Philippe
病毒利用多种宿主细胞机制进行自身复制。这些机制可以作为抗病毒治疗的靶点。宿主靶向治疗可能具有高耐药性屏障。亲环素抑制剂在治疗慢性丙型肝炎方面显示出希望。亲环素抑制剂可能用于治疗其他病毒感染。病毒生命周期的每一步都依赖于宿主，这可能是抗病毒靶点。然而，从历史上看，药物发现主要集中在病毒靶点上，因为它们被认为是特异性的。由于担心潜在的靶向毒性、缺乏预测性细胞培养和动物模型以及宿主-病毒相互作用的复杂性，寻求宿主靶点的努力在很大程度上受到阻碍。另一方面，靶向宿主有明显的优势，例如产生耐药性的高屏障，提供不同基因型/血清型和可能甚至多种病毒的广泛覆盖，以及在可药物化的病毒靶标有限时扩展潜在靶标的列表。以丙型肝炎病毒（HCV）为例，目前有20多种病毒蛋白酶、聚合酶和NS 5A蛋白的抑制剂处于高级临床测试中。然而，耐药性已经成为这些直接作用的抗病毒药物的主要挑战，因为HCV是一种RNA病毒，众所周知易于突变，并且病毒靶点中的单个突变可能会阻止抑制剂的结合，并使其无效。宿主亲环蛋白抑制剂在体外和患者中均显示出有希望的效果，以防止耐药性的出现并治愈HCV感染，无论是单独使用还是与其他药物组合使用。它们还能够阻断许多其他病毒病原体的复制。虽然开发靶向宿主的抗病毒药物的道路很少，而且仍然存在重大挑战，但提供最有效的抗病毒方案，其中可能包括宿主和病毒靶点的抑制剂，应该是值得努力的。
Viruses exploit multiple host cell mechanisms for their own replication. These mechanisms may serve as targets for antiviral therapy. Host-targeted therapies may have a high barrier to resistance. Cyclophilin inhibitors have shown promise in curing chronic hepatitis C. Cyclophilin inhibitors may potentially be used to treat other viral infections. Every step of the viral life cycle is dependent on the host, which potentially can be explored for antiviral targets. Historically, however, drug discovery has focused mainly on viral targets, because of their perceived specificity. Efforts to pursue host targets have been largely hampered by concern over potential on-target toxicity, the lack of predictive cell culture and animal models, and the complexity of host–virus interactions. On the other hand, there are distinct advantages of targeting the host, such as creating a high barrier to resistance, providing broad coverage of different genotypes/serotypes and possibly even multiple viruses, and expanding the list of potential targets, when druggable viral targets are limited. Taking hepatitis C virus (HCV) as the example, there are more than 20 inhibitors of the viral protease, polymerase and NS5A protein currently in advanced clinical testing. However, resistance has become a main challenge with these direct-acting antivirals, because HCV, an RNA virus, is notoriously prone to mutation, and a single mutation in the viral target may prevent the binding of an inhibitor, and rendering it ineffective. Host cyclophilin inhibitors have shown promising effects both in vitro and in patients to prevent the emergence of resistance and to cure HCV infection, either alone or in combination with other agents. They are also capable of blocking the replication of a number of other viral pathogens. While the road to developing host-targeting antivirals has been less traveled, and significant challenges remain, delivering the most effective antiviral regimen, which may comprise inhibitors of both host and viral targets, should be well worth the effort.
登录
查看更多内容
影响因子：
4.8
作者：
Anderson LJ;Lin K;Compton T;Wiedmann B
通讯作者：
Wiedmann B
DOI：
10.1073/pnas.0915117107
发表时间：
2010-02-23
影响因子：
11.1
作者：
Chockalingam, Karuppiah;Simeon, Rudo L.;Chen, Zhilei
通讯作者：
Chen, Zhilei
影响因子：
32.4
作者：
Colgan, J;Asmal, M;Luban, J
通讯作者：
Luban, J
影响因子：
13.5
作者：
Ciesek, Sandra;Steinmann, Eike;Pietschmann, Thomas
通讯作者：
Pietschmann, Thomas
影响因子：
3.8
作者：
de Wilde, Adriaan H.;Zevenhoven-Dobbe, Jessika C.;van Hemert, Martijn J.
通讯作者：
van Hemert, Martijn J.