Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.
Bioorg Med Chem. 2013 Aug 1;21(15):4452-8. doi: 10.1016/j.bmc.2013.05.060. Epub 2013 Jun 5.
To date, several HIV-1 fusion inhibitors based on the carboxy-terminal leucine/isoleucine heptad repeat (CHR) region of an HIV-1 envelope protein gp41 have been discovered. We have shown that a synthetic peptide mimetic of a trimer form of the CHR-derived peptide C34 has potent inhibitory activity against the HIV-1 fusion mechanism, compared to a monomer C34 peptide. The present study revealed that a dimeric form of C34 is evidently structurally critical for fusion inhibitors, and that the activity of multimerized CHR-derived peptides in fusion inhibition is affected by the properties of the unit peptides C34, SC34EK, and T20. The fluorescence-based study suggested that the N36-interactive sites of the C34 trimer, including hydrophobic residues, are exposed outside the trimer and that trimerization of C34 caused a remarkable increase in fusion inhibitory activity. The present results could be useful in the design of fusion inhibitors against viral infections which proceed via membrane fusion with host cells.
迄今为止，已经发现了几种基于 HIV-1 包膜蛋白 gp41 的羧基末端亮氨酸/异亮氨酸七肽重复（CHR）区域的 HIV-1 融合抑制剂。我们已经表明，与单体 C34 肽相比，源自 CHR 的三聚物形式的 C34 模拟肽具有针对 HIV-1 融合机制的强大抑制活性。本研究表明，C34 的二聚体形式对于融合抑制剂显然具有结构上的重要性，并且多聚体 CHR 衍生肽在融合抑制中的活性受单元肽 C34、SC34EK 和 T20 的性质影响。荧光研究表明，C34 三聚体的 N36 相互作用位点，包括疏水性残基，暴露在三聚体之外，并且 C34 的三聚化导致融合抑制活性显著增加。本研究结果可能有助于设计针对通过与宿主细胞融合进行病毒感染的融合抑制剂。
