Abstract
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.
Highlights
Lassa fever is an acute viral hemorrhagic illness occurring in West Africa, having posed a serious public health threat in many countries (Sogoba et al, 2012; Shaffer et al, 2014)
We have previously demonstrated that the N-terminal heptad repeat 1 (HR1) domain binds to C-terminal heptad repeat 2 (HR2) domain to form a stable six-helix bundle (6-HB) to mediate viral entry; peptides derived from HR2 should bind to the homotrimeric HR1, interfering with the formation of 6 helix bundle (6-HB) and, blocking viral entry (Zhu et al, 2015, 2016; Xia et al, 2019)
None of the HR2-derived peptides exhibited significant inhibitory activity on the entry of the Lassa virus (LASV) pseudovirus into the target cell at the concentration as high 100 μM (Figure 5A). These results suggest that the HR2-peptides may not interact with the GP1 protein, which mediates the attachment of LASV to the target cell, the first step of viral entry, and that LASV may not get into the cell through the cytoplasm membrane fusion under neutral pH condition, the second step of entry of some class I enveloped viruses, such as human immunodeficiency virus (HIV) and MERS-CoV (Qi et al, 2017; Su et al, 2017; Xia et al, 2019)
Summary
Lassa fever is an acute viral hemorrhagic illness occurring in West Africa, having posed a serious public health threat in many countries (Sogoba et al, 2012; Shaffer et al, 2014). Its case-fatality rate is 1% for overall infection and 15∼20% for severe cases among patients hospitalized. This mortality rate will increase sharply during epidemics or in pregnant women (Asogun et al, 2012). The New World family mainly contains Venezuelan hemorrhagic fever (VHF), Junín virus (JUNV), Machupo virus (MACV), and Bolivian hemorrhagic fever (BHF), while the Old World viruses includes, for example Lujo virus (LUJV), Lymphocytic choriomeningitis virus (LCMV), Morogoro virus (MORV), and LASV. These arenaviruses have both geographical and genetic differences
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