Institute for Cellular and Molecular Biology, Section of Molecular Genetics and Microbiology, University of Texas at Austin, Austin, TX 78712, USA.
Trends Pharmacol Sci. 2009 Jun;30(6):269-77. doi: 10.1016/j.tips.2009.03.002. Epub 2009 May 8.
The potential threat of a pandemic caused by H5N1 influenza A viruses has stimulated increased research on developing new antivirals against influenza A viruses. Current antivirals are directed against the M2 protein (named adamantanes) and the neuraminidase (named zanamivir and oseltamivir). However, both seasonal and H5N1 influenza A viruses have developed resistance to adamantanes and oseltamivir. Accordingly, new antivirals directed at the M2 and neuraminidase proteins, and against the hemagglutinin protein, are being developed. In addition, elucidation of the structural basis for several crucial functions of other viral proteins (specifically the non-structural NS1A protein, the nucleoprotein and the viral polymerase) has identified novel targets for the development of new antivirals. Here, we describe how functional and structural studies led to the discovery of these novel targets and also how structural information is facilitating the rational design of new drugs against previously identified targets.
H5N1 流感 A 病毒引起大流行的潜在威胁刺激了针对流感 A 病毒开发新抗病毒药物的研究不断增加。目前的抗病毒药物针对 M2 蛋白（称为金刚烷胺）和神经氨酸酶（称为扎那米韦和奥司他韦）。然而，季节性流感 A 病毒和 H5N1 流感 A 病毒均已对金刚烷胺和奥司他韦产生耐药性。因此，正在开发针对 M2 和神经氨酸酶蛋白以及血凝素蛋白的新抗病毒药物。此外，对其他病毒蛋白（特别是非结构 NS1A 蛋白、核蛋白和病毒聚合酶）的几个关键功能的结构基础的阐明，为开发新的抗病毒药物确定了新的靶标。在这里，我们描述了功能和结构研究如何导致这些新靶标的发现，以及结构信息如何促进针对先前确定的靶标的新药的合理设计。
