Z-FA-FMK as a novel potent inhibitor of reovirus pathogenesis and oncolysis in vivo.

Abstract

BACKGROUND:

Respiratory enteric orphan (reo)virus is a promising oncolytic viral candidate. Reoviral anticancer therapy is currently undergoing multiple clinical trials targeting various human cancers; however, there is no effective reoviral inhibitor that can be used to block unwanted reovirus replication during reoviral anticancer therapy.

METHODS:

Studies were conducted with transformed or normal cells in vitro and in vivo to characterize viral replication in the presence or absence of chemical inhibitors.

RESULTS:

We have identified a protease inhibitor that is very effective in the inhibition of viral replication. The dipeptide benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone (Z-FA-FMK) effectively inhibited reovirus replication in a susceptible host and cured cells of a persistent infection with reovirus in vitro. Electron microscopic analysis of Z-FA-FMK-treated cells revealed that internalized reovirus virions, retained in a perinuclear localization, no longer undergo further processing into viral factories following Z-FA-FMK treatment, suggesting that Z-FA-FMK specifically affects a reovirus virion maturation step. Animal studies showed that reovirus infection of Ras oncogenic tumours and host heart tissues is completely blocked by Z-FA-FMK treatment in severe combined immunodeficiency mice.

CONCLUSIONS:

Z-FA-FMK is a very effective viral inhibitor that can prevent reovirus replication in vitro and reovirus-mediated myocarditis, as well as reovirus-mediated oncolysis, in vivo. A potential application of this drug for inhibition of reovirus infection is suggested.

• Authors: Manbok Kim, Kristina K Hansen, Lesley Davis, Guido van Marle, Michael John Gill, Julie D Fox, Morley D Hollenberg, Derrick E Rancourt, Patrick W K Lee, Chae-Ok Yun, Randal N Johnston
• Journal: Antiviral therapy (Antivir Ther) Vol. 15 Issue 6 Pg. 897-905 ( 2010) ISSN: 2040-2058 [Electronic] England
• PMID: 20834102 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Cysteine Proteinase Inhibitors
• Dipeptides
• Ketones
• MDL 201053

Topics

• Animals
• Antiviral Agents (therapeutic use)
• Capsid (drug effects, physiology, virology)
• Cell Line
• Cysteine Proteinase Inhibitors (therapeutic use)
• Dipeptides (therapeutic use)
• Genes, ras
• Humans
• Ketones (therapeutic use)
• Mice
• Mice, SCID
• Oncolytic Viruses (drug effects, pathogenicity)
• Reoviridae (drug effects, pathogenicity, physiology)
• Reoviridae Infections (therapy)
• Virus Replication (drug effects)