Takahara Aoi, Nakatsu Toru, Hirata Kazushige, Hayashi Hironori, Kawaji Kumi, Aoki Keisuke, Inuki Shinsuke, Ohno Hiroaki, Kato Hiroaki, Kodama Eiichi, Oishi Shinya
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
School of Pharmaceutical Sciences, Wakayama Medical University, 25-1 Shichibancho, Wakayama 640-8156, Japan.
J Med Chem. 2025 Feb 13;68(3):3123-3133. doi: 10.1021/acs.jmedchem.4c02337. Epub 2025 Jan 31.
Measles is a highly infectious disease and remains a major cause of childhood mortality worldwide. In some cases, the measles virus (MV) induces subacute sclerosing panencephalitis within several years of the acute infection. The infection of the target cells by MV is mediated by the F protein, in which two heptad repeat regions, HR1 and HR2, form a six-helix bundle before membrane fusion. We previously reported anti-MV peptides, which were designed from the HR region of the MV F protein. Here, we characterized the essential interactions between the HR1 and HR2 regions on the postfusion six-helix bundles of synthetic HR1 and HR2 peptides by crystallographic studies. Based on the crystal structures, we identified the minimal α-helix sequence for antiviral activity. Additionally, optimizing HR2 peptides by introducing α-helix-inducible motifs and maintaining key hydrogen bond networks at the N- and C-terminal regions led to the identification of highly potent antiviral peptides.
麻疹是一种高度传染性疾病，仍然是全球儿童死亡的主要原因。在某些情况下，麻疹病毒（MV）在急性感染后的几年内会诱发亚急性硬化性全脑炎。MV对靶细胞的感染由F蛋白介导，其中两个七肽重复区域HR1和HR2在膜融合前形成六螺旋束。我们之前报道了从MV F蛋白的HR区域设计的抗MV肽。在这里，我们通过晶体学研究表征了合成HR1和HR2肽的融合后六螺旋束上HR1和HR2区域之间的关键相互作用。基于晶体结构，我们确定了抗病毒活性的最小α螺旋序列。此外，通过引入α螺旋诱导基序并在N端和C端区域维持关键氢键网络来优化HR2肽，从而鉴定出高效抗病毒肽。
