Differential inhibition of HIV-1 and SIV envelope-mediated cell fusion by C34 peptides derived from the C-terminal heptad repeat of gp41 from diverse strains of HIV-1, HIV-2, and SIV
Differential inhibition of HIV-1 and SIV envelope-mediated cell fusion by C34 peptides derived from the C-terminal heptad repeat of gp41 from diverse strains of HIV-1, HIV-2, and SIV
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DOI：
10.1021/jm049026h
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发表时间：
2005-04-21
影响因子：
7.3
通讯作者：
Clore, GM
中科院分区：
文献类型：
--
作者：
Gustchina, E;Hummer, G;Clore, GM
C34抑制人（HIV）和猿猴（SIV）免疫缺陷病毒包膜（Env）介导的细胞融合的谱，C34是对应于gp 41的C-七肽重复的34个残基的肽（HIV-1 Env的残基628-661），已经使用一组五种包膜糖蛋白进行了检测，其中三种来自HIV-1（LAV，SF 162和89.6）和两种来自SIV（mac 239和mac 316）的C34肽，以及六种来自三种HIV-1毒株（LAV，N CM和0 CM），两种HIV-2毒株（EHO和ALI）和一种SIV毒株（非洲绿色猴，AGM）的C34肽。采用基于牛痘的定量报告基因细胞融合测定。来自30种C34/包膜糖蛋白组合的抑制数据，其可以拟合成简单的活性关系，其中IC 50值跨越从4 nM至70 μ M的超过4个数量级的范围，允许人们根据计算的C34肽和N-乙酰氨基酚之间的相互作用自由能来合理化C34肽的抑制性质的效力和广泛性。gp 41的螺旋三聚体卷曲螺旋和游离C34肽的螺旋倾向。特别令人感兴趣的是，发现来源于HIV-2的EHO株的C34肽是Env介导的细胞融合的广谱、高效抑制剂，在所测试的整个HIV-1和SIV包膜糖蛋白组中，IC 50值跨越仅4至25 nM的非常窄的范围。这一结果表明，来自HIV-2 EHO的C34可能是针对HIV-1的多种和/或耐药株的潜在有用的治疗剂。
The spectrum of inhibition of human (HIV) and simian (SIV) immunodeficiency virus envelope (Env)-mediated cell fusion by C34, a 34 residue peptide corresponding to the C-heptad repeat of gp41 (residues 628-661 of HIV-1 Env), has been examined using a panel of five envelope glycoproteins, three from HIV-1 (LAV, SF162 and 89.6) and two from SIV (mac239 and mac316), and six C34 peptides derived from three strains of HIV-1 (LAV, N CM, and 0 CM), two strains of HIV-2 (EHO and ALI), and one strain of SIV (African Green Monkey, AGM). A quantitative vaccinia-based reporter gene cell fusion assay was employed. The inhibition data from the panel of 30 C34/envelope glycoprotein combinations, which can be fit to a simple activity relationship with IC50 values spanning a range of over 4 orders of magnitude from 4 nM to 70 mu M, permits one to rationalize both the potency and broadness of the inhibitory properties of the C34 peptides in terms of computed interaction free energies between the C34 peptides and the N-helical trimeric coiled-coil of gp41 and the helical propensities of the free C34 peptides. Of particular interest is the finding that the C34 peptide derived from the EHO strain of HIV-2 is a broad spectrum, highly potent inhibitor of Env-mediated cell fusion with IC50 values spanning a very narrow range from only 4 to 25 nM over the entire panel of HIV-1 and SIV envelope glycoproteins tested. This result suggests that C34 from HIV-2 EHO may present a potentially useful therapeutic agent against diverse and/or resistant strains of HIV-1.