Molecular determinants of antiviral potency of paramyxovirus entry inhibitors.

Abstract

Hendra virus (HeV) and Nipah virus (NiV) constitute the Henipavirus genus of paramyxoviruses, both fatal in humans and with the potential for subversion as agents of bioterrorism. Binding of the HeV/NiV attachment protein (G) to its receptor triggers a series of conformational changes in the fusion protein (F), ultimately leading to formation of a postfusion six-helix bundle (6HB) structure and fusion of the viral and cellular membranes. The ectodomain of paramyxovirus F proteins contains two conserved heptad repeat regions, the first (the N-terminal heptad repeat [HRN]) adjacent to the fusion peptide and the second (the C-terminal heptad repeat [HRC]) immediately preceding the transmembrane domain. Peptides derived from the HRN and HRC regions of F are proposed to inhibit fusion by preventing activated F molecules from forming the 6HB structure that is required for fusion. We previously reported that a human parainfluenza virus 3 (HPIV3) F peptide effectively inhibits infection mediated by the HeV glycoproteins in pseudotyped-HeV entry assays more effectively than the comparable HeV-derived peptide, and we now show that this peptide inhibits live-HeV and -NiV infection. HPIV3 F peptides were also effective in inhibiting HeV pseudotype virus entry in a new assay that mimics multicycle replication. This anti-HeV/NiV efficacy can be correlated with the greater potential of the HPIV3 C peptide to interact with the HeV F N peptide coiled-coil trimer, as evaluated by thermal unfolding experiments. Furthermore, replacement of a buried glutamic acid (glutamic acid 459) in the C peptide with valine enhances antiviral potency and stabilizes the 6HB conformation. Our results strongly suggest that conserved interhelical packing interactions in the F protein fusion core are important determinants of C peptide inhibitory activity and offer a strategy for the development of more-potent analogs of F peptide inhibitors.

• Authors: M Porotto, P Carta, Y Deng, G E Kellogg, M Whitt, M Lu, B A Mungall, A Moscona
• Journal: Journal of virology (J Virol) Vol. 81 Issue 19 Pg. 10567-74 (Oct 2007) ISSN: 0022-538X [Print] United States
• PMID: 17652384 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• P protein, Human parainfluenza virus 3
• Peptides
• Phosphoproteins
• Viral Envelope Proteins
• Viral Proteins

Topics

• Amino Acid Sequence
• Antiviral Agents (chemistry, pharmacology)
• Cell Line
• Conserved Sequence
• Hendra Virus (drug effects, physiology)
• Henipavirus (drug effects, physiology)
• Humans
• Molecular Mimicry
• Molecular Sequence Data
• Mutation
• Nipah Virus (drug effects, physiology)
• Paramyxovirinae (drug effects)
• Peptides (chemistry, genetics, pharmacology)
• Phosphoproteins (chemistry, genetics, pharmacology)
• Viral Envelope Proteins (antagonists & inhibitors, chemistry, genetics)
• Viral Proteins (chemistry, genetics, pharmacology)
• Virus Internalization (drug effects)