Biochemistry and biophysics of HIV-1 gp41 - membrane interactions and implications for HIV-1 envelope protein mediated viral-cell fusion and fusion inhibitor design.
Biochemistry and biophysics of HIV-1 gp41 - membrane interactions and implications for HIV-1 envelope protein mediated viral-cell fusion and fusion inhibitor design.
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DOI：
10.2174/156802611798808497
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发表时间：
2011-12
影响因子：
3.4
通讯作者：
Liu K
中科院分区：
文献类型：
--
作者：
Cai L;Gochin M;Liu K
人类免疫缺陷病毒1型(HIV-1)是获得性免疫缺陷综合征(AIDS)的病原体，每年造成约200万人死亡，至今仍没有有效的疫苗。HIV-1通过包膜蛋白介导的病毒-细胞融合感染宿主细胞。囊膜蛋白的跨膜亚单位gp41是促进融合的分子机制。其胞外结构域包括融合肽(FP)、N端七肽重复序列(NHR)、C端七肽重复序列(CHR)和膜近端胞外区(MPER)。在融合过程中，FP插入宿主细胞膜，延伸的gp41前发夹构象分别通过MPER和FP连接病毒膜和细胞膜。不稳定的前发夹的后续构象变化导致在NHR和CHR之间形成卷曲的6-螺旋束(6HB)结构。6HB形成的能量学驱动了膜的对位和融合。靶向gp41功能区以防止6HB形成的药物可抑制HIV-1感染。T20(恩福韦肽，Fuzeon)于2003年被美国FDA批准为第一个融合抑制剂。它是来自gp41CHR的一个36个残基的多肽，它通过靶向NHR和脂质来抑制6HB的形成。鼓励开发新的融合抑制剂，特别是小分子药物，以克服T20作为多肽药物的缺点。疏水特性和膜结合对gp41的功能和作用机制至关重要。为了更好地了解gp41介导的病毒-细胞融合，以指导或指导新的HIV-1融合抑制剂的设计，本文综述了利用与特定功能结构域相对应的多肽或包含多个相互作用结构域的结构物来研究gp41与膜的相互作用。
Human immunodeficiency virus type 1 (HIV-1), the pathogen of acquired immunodeficiency syndrome (AIDS), causes ~2 millions death every year and still defies an effective vaccine. HIV-1 infects host cells through envelope protein – mediated virus-cell fusion. The transmembrane subunit of envelope protein, gp41, is the molecular machinery which facilitates fusion. Its ectodomain contains several distinguishing functional domains, fusion peptide (FP), N-terminal heptad repeat (NHR), C-terminal heptad repeat (CHR) and membrane proximal extracellular region (MPER). During the fusion process, FP inserts into the host cell membrane, and an extended gp41 prehairpin conformation bridges the viral and cell membranes through MPER and FP respectively. Subsequent conformational change of the unstable prehairpin results in a coiled-coil 6-helix bundle (6HB) structure formed between NHR and CHR. The energetics of 6HB formation drives membrane apposition and fusion. Drugs targeting gp41 functional domains to prevent 6HB formation inhibit HIV-1 infection. T20 (enfuvirtide, Fuzeon) was approved by the US FDA in 2003 as the first fusion inhibitor. It is a 36-residue peptide from the gp41 CHR, and it inhibits 6HB formation by targeting NHR and lipids. Development of new fusion inhibitors, especially small molecule drugs, is encouraged to overcome the shortcomings of T20 as a peptide drug. Hydrophobic characteristics and membrane association are critical for gp41 function and mechanism of action. Research in gp41-membrane interactions, using peptides corresponding to specific functional domains, or constructs including several interactive domains, are reviewed here to get a better understanding of gp41 mediated virus-cell fusion that can inform or guide the design of new HIV-1 fusion inhibitors.
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