Jin B S, Ryu J R, Ahn K, Yu Y G
Structural Biology Center, Korea Institute of Science and Technology, Cheongryang, Seoul, South Korea.
AIDS Res Hum Retroviruses. 2000 Nov 20;16(17):1797-804. doi: 10.1089/08892220050195757.
Fusion between the envelope of HIV and the plasma membrane of target cells is mediated by gp41, the envelope glycoprotein of HIV. Peptides derived from the membrane-proximal helical motif of the extracellular domain of gp41 effectively inhibit the infection of HIV, and their inhibitory activities are known to be correlated with the helical propensity of the peptides. We have designed small peptides that can form a stable alpha helix and thereby inhibit gp120/41-mediated cell fusion. A 19-mer peptide from the membrane-proximal helical motif of gp41 had no secondary structure in solution, and failed to block gp41-mediated cell fusion. When amino acids with low helical propensity were substituted, and helix-capping sequences were introduced at both ends of the peptides, the modified peptides formed a stable helical structure. They also bound to the coiled-coil motif of gp41 presented at the C terminus of thioredoxin and blocked the cell fusion mediated by gp120/41. These results implied that such modification was enough to change a short peptide derived from gp41 into a potent inhibitor against the infection of HIV.
HIV包膜与靶细胞的质膜之间的融合由HIV包膜糖蛋白gp41介导。源自gp41胞外结构域膜近端螺旋基序的肽可有效抑制HIV感染，且已知其抑制活性与肽的螺旋倾向相关。我们设计了能够形成稳定α螺旋从而抑制gp120/41介导的细胞融合的小肽。来自gp41膜近端螺旋基序的19聚体肽在溶液中没有二级结构，无法阻断gp41介导的细胞融合。当替换螺旋倾向低的氨基酸，并在肽的两端引入螺旋封端序列时，修饰后的肽形成了稳定的螺旋结构。它们还与硫氧还蛋白C端呈现的gp41的卷曲螺旋基序结合，并阻断了gp120/41介导的细胞融合。这些结果表明，这种修饰足以将源自gp41的短肽转变为抗HIV感染的有效抑制剂。
