Specific targeting of the F13L protein by ST-246 affects orthopoxvirus production differently.

Abstract

BACKGROUND:

ST-246 is a potent anti-orthopoxviral molecule targeting the F13L protein of vaccinia virus, which is involved in the wrapping of viruses. The discrepancy in sensitivities of several orthopoxviruses to ST-246 has raised questions about potential differences in their replicative cycles and/or the presence of another drug target.

METHODS:

Density gradients were used to evaluate the differences between the viral cycles of vaccinia, cowpox and camelpox viruses. Also, to investigate if ST-246 inhibits a single target, we compared its activity to that of small interfering RNAs designed to silence the F13L gene (siF13Ls).

RESULTS:

We showed that the spread of vaccinia virus involved both intracellular and extracellular enveloped viruses, whereas both cowpox and camelpox viruses seemed to propagate via non-enveloped intracellular forms and cell-associated viral particles. Although ST-246 exerted a clear antiviral activity by interfering with the egress of the virus from infected cells, we observed that cowpox and camelpox viruses, in contrast to vaccinia virus, could be directed towards a lytic cycle under ST-246 treatment. We specifically knocked down the F13L transcripts of vaccinia and camelpox viruses by > 85%, reduced virus progeny by 90% and showed that siF13Ls affect camelpox and vaccinia virus propagation differently. Flow cytometry data validated that ST-246 interfered with the activity of the F13L protein, whereas siF13Ls silenced the F13L gene.

CONCLUSIONS:

Our observations support that vaccinia, cowpox and camelpox viruses exhibit different levels of sensitivity to ST-246 because of dissimilarities between their ways of propagation, and provide a better understanding of the mode of action of ST-246.

• Authors: Sophie Duraffour, Solenne Vigne, Kurt Vermeire, Aude Garcel, Els Vanstreels, Dirk Daelemans, Guang Yang, Robert Jordan, Dennis E Hruby, Jean-Marc Crance, Daniel Garin, Graciela Andrei, Robert Snoeck
• Journal: Antiviral therapy (Antivir Ther) Vol. 13 Issue 8 Pg. 977-90 ( 2008) ISSN: 1359-6535 [Print] England
• PMID: 19195323 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Benzamides
• Isoindoles
• Membrane Proteins
• RNA, Small Interfering
• Viral Envelope Proteins
• p37 protein, Vaccinia virus
• tecovirimat

Topics

• Antiviral Agents (pharmacology)
• Benzamides (pharmacology)
• Cell Line
• Cowpox virus (drug effects)
• Gene Silencing
• Humans
• Isoindoles (pharmacology)
• Membrane Proteins (metabolism)
• Orthopoxvirus (drug effects)
• RNA, Small Interfering
• Species Specificity
• Vaccinia virus (drug effects)
• Viral Envelope Proteins (metabolism)
• Virus Replication (drug effects)