Inhibition of Ebola virus entry by a C-peptide targeted to endosomes

Emily Happy Miller, Joseph S. Harrison, Sheli R. Radoshitzky, Chelsea D. Higgins, Xiaoli Chi, Lian Dong, Jens H. Kuhn, Sina Bavari, Jonathan R. Lai, Kartik Chandran

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Ebola virus (EboV) and Marburg virus (MarV) (filoviruses) are the causative agents of severe hemorrhagic fever. Infection begins with uptake of particles into cellular endosomes, where the viral envelope glycoprotein (GP) catalyzes fusion between the viral and host cell membranes. This fusion event is thought to involve conformational rearrangements of the transmembrane subunit (GP2) of the envelope spike that ultimately result in formation of a six-helix bundle by the N- and C-terminal heptad repeat (NHR and CHR, respectively) regions of GP2. Infection by other viruses employing similar viral entry mechanisms (such as HIV-1 and severe acute respiratory syndrome coronavirus) can be inhibited with synthetic peptides corresponding to the native CHR sequence ("C- peptides"). However, previously reported EboV C-peptides have shown weak or insignificant antiviral activity. To determine whether the activity of a C-peptide could be improved by increasing its intracellular concentration, we prepared an EboV C-peptide conjugated to the arginine-rich sequence from HIV-1 Tat, which is known to accumulate in endosomes. We found that this peptide specifically inhibited viral entry mediated by filovirus GP proteins and infection by authentic filoviruses. We determined that antiviral activity was dependent on both the Tat sequence and the native EboV CHR sequence. Mechanistic studies suggested that the peptide acts by blocking a membrane fusion intermediate.

Original languageEnglish (US)
Pages (from-to)15854-15861
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number18
DOIs
StatePublished - May 6 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Miller, E. H., Harrison, J. S., Radoshitzky, S. R., Higgins, C. D., Chi, X., Dong, L., Kuhn, J. H., Bavari, S., Lai, J. R., & Chandran, K. (2011). Inhibition of Ebola virus entry by a C-peptide targeted to endosomes. Journal of Biological Chemistry, 286(18), 15854-15861. https://doi.org/10.1074/jbc.M110.207084