A synthetic peptide inhibitor of human immunodeficiency virus replication: correlation between solution structure and viral inhibition.
A synthetic peptide inhibitor of human immunodeficiency virus replication: correlation between solution structure and viral inhibition.
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DOI：
10.1073/pnas.89.21.10537
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发表时间：
1992-11
影响因子：
11.1
通讯作者：
C. Wild;T. Oas;C. McDanal;D. Bolognesi;T. Matthews
中科院分区：
文献类型：
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作者：
C. Wild;T. Oas;C. McDanal;D. Bolognesi;T. Matthews
合成了一种命名为DP-107的肽，其含有人免疫缺陷病毒1型毒株LAI（HIV-1LAI）包膜糖蛋白gp160的氨基酸残基558 - 595。二级结构的算法预测，包膜跨膜蛋白的这一区域应形成延伸的α-螺旋。与该预测一致，圆二色性（CD）分析表明，在生理条件下，DP-107约为85%螺旋。这种大小的合成肽中高度稳定的二级结构表明了卷曲螺旋或亮氨酸拉链典型的自缔合。在生物测定中，该肽有效地阻断了病毒介导的细胞-细胞融合过程以及HIV-1原型和原代分离株对外周血单核细胞的感染。一个单一的氨基酸取代的肽大大不稳定的溶液结构，通过CD和废除其抗病毒活性。含有末端半胱氨酸的类似物被氧化形成二聚体，这种修饰将抗病毒作用所需的剂量从5微克/毫升降低到约1微克/毫升。这些结果表明，寡聚化和有序结构是必要的生物活性。他们还提供了对该区域在HIV感染中的作用以及开发一类新的抗病毒剂的潜力的见解。
A peptide designated DP-107 was synthesized containing amino acid residues 558-595 of the envelope glycoprotein gp160 of human immunodeficiency virus type 1 strain LAI (HIV-1LAI). Algorithms for secondary structure have predicted that this region of the envelope transmembrane protein should form an extended alpha-helix. Consistent with this prediction, analysis by circular dichroism (CD) indicated that, under physiological conditions, DP-107 is approximately 85% helical. The high degree of stable secondary structure in a synthetic peptide of this size suggests self-association typical of a coiled coil or leucine zipper. In biological assays, the peptide efficiently blocked virus-mediated cell-cell fusion processes as well as infection of peripheral blood mononuclear cells by both prototypic and primary isolates of HIV-1. A single amino acid substitution in the peptide greatly destabilized its solution structure as measured by CD and abrogated its antiviral activity. An analogue containing a terminal cysteine was oxidized to form a dimer, and this modification lowered the dose required for antiviral effect from 5 to about 1 microgram/ml. These results suggest that both oligomerization and ordered structure are necessary for biological activity. They provide insights also into the role of this region in HIV infection and the potential for development of a new class of antiviral agents.