Zhang Xuejiao, Wang Cong, Chen Baohua, Wang Qian, Xu Wei, Ye Sheng, Jiang Shibo, Zhu Yun, Zhang Rongguang
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
Front Microbiol. 2019 Aug 13;10:1829. doi: 10.3389/fmicb.2019.01829. eCollection 2019.
The envelope glycoproteins GP1 and GP2 of Lassa virus (LASV) bind to the host cell receptors to mediate viral infection. So far, no approved vaccines and specific treatment options against LASV exist. To develop specific fusion inhibitors against LASV, we solved the crystal structure of the post-fusion 6 helix bundle (6-HB) formed by two heptad repeat domains (HR1 and HR2) of GP2. This fusion core contains a parallel trimeric coiled-coil of three HR1 helices, around which three HR2 helices are entwined in an antiparallel manner. Various hydrophobic and charged interactions form between HR1 and HR2 domains to stabilize the overall conformation of GP2 fusion core. Based on the structure, we designed several peptides spanning the HR2 domain and tested their antiviral activities. We found that the longer HR2 peptides were effective in inhibiting LASV GPC protein-mediated cell-cell fusion under low pH condition. These results not only suggest that LASV infects the target cell mainly through endocytosis, including micropinocytosis, and membrane fusion at low pH, but also provide an important basis for rational design of LASV fusion inhibitors.
拉沙病毒（LASV）的包膜糖蛋白GP1和GP2与宿主细胞受体结合以介导病毒感染。到目前为止，尚无针对LASV的获批疫苗和特异性治疗方案。为了开发针对LASV的特异性融合抑制剂，我们解析了由GP2的两个七肽重复结构域（HR1和HR2）形成的融合后6螺旋束（6-HB）的晶体结构。这个融合核心包含由三个HR1螺旋组成的平行三聚体卷曲螺旋，三个HR2螺旋以反平行方式缠绕在其周围。HR1和HR2结构域之间形成各种疏水和带电相互作用，以稳定GP2融合核心的整体构象。基于该结构，我们设计了几种跨越HR2结构域的肽，并测试了它们的抗病毒活性。我们发现，较长的HR2肽在低pH条件下可有效抑制LASV GPC蛋白介导的细胞-细胞融合。这些结果不仅表明LASV主要通过内吞作用（包括微胞饮作用）以及在低pH下的膜融合感染靶细胞，而且为合理设计LASV融合抑制剂提供了重要依据。
