A Fusion-Inhibiting Peptide against Rift Valley Fever Virus Inhibits Multiple, Diverse Viruses

Jeffrey W Koehler,Mary C Guttieri,Catherine V Badger,Shannon L Taylor,Rebecca J Grant,Connie S Schmaljohn,Kristin W Spik,Jeffrey M Smith,Monica M Ogg,Anders Wallqvist,Daniel R Ripoll,Robert F Garry,Brian Bird

doi:10.1371/journal.pntd.0002430

Abstract

For enveloped viruses, fusion of the viral envelope with a cellular membrane is critical for a productive infection to occur. This fusion process is mediated by at least three classes of fusion proteins (Class I, II, and III) based on the protein sequence and structure. For Rift Valley fever virus (RVFV), the glycoprotein Gc (Class II fusion protein) mediates this fusion event following entry into the endocytic pathway, allowing the viral genome access to the cell cytoplasm. Here, we show that peptides analogous to the RVFV Gc stem region inhibited RVFV infectivity in cell culture by inhibiting the fusion process. Further, we show that infectivity can be inhibited for diverse, unrelated RNA viruses that have Class I (Ebola virus), Class II (Andes virus), or Class III (vesicular stomatitis virus) fusion proteins using this single peptide. Our findings are consistent with an inhibition mechanism similar to that proposed for stem peptide fusion inhibitors of dengue virus in which the RVFV inhibitory peptide first binds to both the virion and cell membranes, allowing it to traffic with the virus into the endocytic pathway. Upon acidification and rearrangement of Gc, the peptide is then able to specifically bind to Gc and prevent fusion of the viral and endocytic membranes, thus inhibiting viral infection. These results could provide novel insights into conserved features among the three classes of viral fusion proteins and offer direction for the future development of broadly active fusion inhibitors.

Highlights

Rift Valley fever (RVF) is a disease of major public health and economic concern, affecting humans and livestock throughout Africa [1,2,3,4,5,6] and the Arabian Peninsula [7]
We synthesized peptides based on the Rift Valley fever virus (RVFV) fusion protein stem region and tested the peptides for their ability to prevent RVFV infection of cell cultures
We found that one of these peptides was able to inhibit RVFV infectivity by preventing the fusion process and that this peptide had broad activity against other RNA viruses including Ebola, Andes, and vesicular stomatitis viruses

Summary

Introduction

Rift Valley fever (RVF) is a disease of major public health and economic concern, affecting humans and livestock throughout Africa [1,2,3,4,5,6] and the Arabian Peninsula [7]. The etiological agent of this zoonosis, Rift Valley fever virus (RVFV), is an arbovirus belonging to the Phlebovirus genus in the family Bunyaviridae. RVFV infection is severe in animals, especially sheep, cattle, and goats, resulting in high mortality rates in newborns and near 100% abortion rates in pregnant animals. Infection is usually self-limiting, but a small percent of cases (1–2%) can progress to severe hepatitis with hemorrhagic manifestations. RVFV entry into permissive cells is mediated by Gn and Gc, with Gc being a class II fusion protein [8,9] that uses a low pH-dependent fusion mechanism following endocytosis [10]

Methods

Results

Discussion

Conclusion