Gustchina Elena, Louis John M, Bewley Carole A, Clore G Marius
Laboratory of Chemical Physics, Building 5, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA.
J Mol Biol. 2006 Dec 1;364(3):283-9. doi: 10.1016/j.jmb.2006.09.017. Epub 2006 Sep 12.
The human immunodeficiency virus type-1 (HIV-1) envelope (Env) proteins that mediate membrane fusion represent a major target for the development of new AIDS therapies. Three classes of Env-mediated membrane fusion inhibitors have been described that specifically target the pre-hairpin intermediate conformation of gp41. Class 2 inhibitors bind to the C-terminal heptad repeat (C-HR) of gp41. The single example of a class 3 inhibitor targets the trimeric N-terminal heptad repeat (N-HR) of gp41 and has been postulated to sequestrate the N-HR of the pre-hairpin intermediate through the formation of fusion incompetent heterotrimers. Here, we show that N(CCG)-gp41, a class 2 inhibitor, and N36(Mut(e,g)), a class 3 inhibitor, synergistically inhibit Env-mediated membrane fusion for several representative HIV-1 strains (X4 and R5) in both a cell fusion assay (with membrane-bound CD4) and an Env-pseudo-typed virus neutralization assay. The mechanistic, as well as potential therapeutic, implications of these observations for HIV-Env-mediated membrane fusion are discussed.
介导膜融合的人类免疫缺陷病毒1型（HIV-1）包膜（Env）蛋白是开发新型艾滋病疗法的主要靶点。已描述了三类Env介导的膜融合抑制剂，它们特异性靶向gp41的前发夹中间体构象。2类抑制剂与gp41的C端七肽重复序列（C-HR）结合。3类抑制剂的唯一实例靶向gp41的三聚体N端七肽重复序列（N-HR），并推测通过形成无融合能力的异源三聚体来隔离前发夹中间体的N-HR。在此，我们表明，2类抑制剂N(CCG)-gp41和3类抑制剂N36(Mut(e,g))在细胞融合试验（使用膜结合CD4）和Env假型病毒中和试验中，对几种代表性HIV-1毒株（X4和R5）均能协同抑制Env介导的膜融合。本文讨论了这些观察结果对HIV-Env介导的膜融合的机制及潜在治疗意义。
