Menéndez-Arias Luis, Gago Federico
Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), c/Nicolás Cabrera 1, Campus de Cantoblanco, 28049, Madrid, Spain,
Subcell Biochem. 2013;68:599-630. doi: 10.1007/978-94-007-6552-8_20.
During the last 30 years, significant progress has been made in the development of novel antiviral drugs, mainly crystallizing in the establishment of potent antiretroviral therapies and the approval of drugs inhibiting hepatitis C virus replication. Although major targets of antiviral intervention involve intracellular processes required for the synthesis of viral proteins and nucleic acids, a number of inhibitors blocking virus assembly, budding, maturation, entry or uncoating act on virions or viral capsids. In this review, we focus on the drug discovery process while presenting the currently used methodologies to identify novel antiviral drugs by using a computer-based approach. We provide examples illustrating structure-based antiviral drug development, specifically neuraminidase inhibitors against influenza virus (e.g. oseltamivir and zanamivir) and human immunodeficiency virus type 1 protease inhibitors (i.e. the development of darunavir from early peptidomimetic compounds such as saquinavir). A number of drugs in preclinical development acting against picornaviruses, hepatitis B virus and human immunodeficiency virus and their mechanism of action are presented to show how viral capsids can be exploited as targets of antiviral therapy.
在过去30年里，新型抗病毒药物的研发取得了重大进展，主要体现在强效抗逆转录病毒疗法的建立以及抑制丙型肝炎病毒复制的药物获批上市。尽管抗病毒干预的主要靶点涉及病毒蛋白和核酸合成所需的细胞内过程，但一些阻断病毒组装、出芽、成熟、进入或脱壳的抑制剂作用于病毒粒子或病毒衣壳。在本综述中，我们在介绍当前使用的基于计算机方法识别新型抗病毒药物的方法时，重点关注药物发现过程。我们提供了基于结构的抗病毒药物开发的实例，特别是针对流感病毒的神经氨酸酶抑制剂（如奥司他韦和扎那米韦）以及1型人类免疫缺陷病毒蛋白酶抑制剂（即从早期拟肽化合物如沙奎那韦开发出地瑞那韦）。还介绍了一些处于临床前开发阶段、作用于小核糖核酸病毒、乙型肝炎病毒和人类免疫缺陷病毒的药物及其作用机制，以展示病毒衣壳如何能够被用作抗病毒治疗的靶点。
