Debnath Asim K
Lindsley F Kimball Research Institute of the New York Blood Center, Laboratory of Molecular Modeling & Drug Design, New York, NY 10021, USA.
Curr Opin Investig Drugs. 2006 Feb;7(2):118-27.
Class I viral fusion proteins have an important role in the fusion of viral membranes with host cell membranes, a critical step in the viral life-cycle. These proteins all have similar structural features and form six-helix bundles in their fusogenic form, a general mechanism of action for virus-cell fusion. The successful discovery of peptide-based inhibitors of fusion proteins, in addition to the US Food and Drug Administration approval of one of these inhibitors as an anti-HIV-1 drug, confirmed that the inhibition of six-helix bundle formation is a viable strategy for identifying antiviral drugs. Because peptide-based drugs have several limitations, research has been undertaken to identify potent small-molecule inhibitors of six-helix bundle formation in a variety of viruses, including HIV-1, human respiratory syncytial virus and measles virus. Small-molecule inhibitors that disrupt six-helix bundle formation and prevent viral infection have been identified. This review will focus on the discovery of these small-molecule inhibitors.
I类病毒融合蛋白在病毒膜与宿主细胞膜的融合过程中发挥着重要作用，这是病毒生命周期中的关键步骤。这些蛋白都具有相似的结构特征，在其融合形式下形成六螺旋束，这是病毒与细胞融合的一般作用机制。基于肽的融合蛋白抑制剂的成功发现，以及美国食品药品监督管理局对其中一种抑制剂作为抗HIV-1药物的批准，证实了抑制六螺旋束形成是一种可行的抗病毒药物识别策略。由于基于肽的药物存在若干局限性，因此人们开展了研究，以确定包括HIV-1、人呼吸道合胞病毒和麻疹病毒在内的多种病毒中六螺旋束形成的有效小分子抑制剂。已经鉴定出能够破坏六螺旋束形成并预防病毒感染的小分子抑制剂。本综述将聚焦于这些小分子抑制剂的发现。
