Elucidation of Postfusion Structures of the Measles Virus F Protein for the Structure-Based Design of Fusion Inhibitors

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.

麻疹是一种高传染性疾病，至今仍是全球范围内导致儿童死亡的主要病因之一。在部分病例中，麻疹病毒（Measles Virus, MV）可在急性感染后的数年内诱发亚急性硬化性全脑炎（Subacute Sclerosing Panencephalitis）。MV对靶细胞的感染由F蛋白（Fusion Protein, F）介导，该蛋白包含两个七肽重复区：七肽重复区1（Heptad Repeat 1, HR1）与七肽重复区2（Heptad Repeat 2, HR2），二者可在膜融合前形成六螺旋束。我们此前曾报道过基于MV F蛋白HR区设计的抗MV多肽。本研究通过晶体学实验，解析了合成HR1与HR2多肽所形成的融合后六螺旋束上HR1与HR2区域之间的核心相互作用特征。基于该晶体结构，我们确定了具备抗病毒活性的最小α-螺旋（alpha-helix）序列。此外，我们通过引入α螺旋诱导基序，并保留其氨基端（N-terminal）与羧基端（C-terminal）区域的关键氢键网络对HR2多肽进行优化，最终筛选得到强效抗病毒多肽。