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

 Manbok Kim  ;  Kristina K Hansen  ;  Lesley Davis  ;  Guido van Marle  ;  Michael John Gill  ;  Julie D Fox  ;  Morley D Hollenberg  ;  Derrick E Rancourt  ;  Patrick WK Lee  ;  Chae-Ok Yun  ;  Randal N Johnston 
 ANTIVIRAL THERAPY, Vol.15(6) : 897-905, 2010 
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Animals ; Antiviral Agents/therapeutic use ; Capsid/drug effects ; Capsid/physiology ; Capsid/virology ; Cell Line ; Cysteine Proteinase Inhibitors/therapeutic use* ; Dipeptides/therapeutic use* ; Genes, ras ; Humans ; Ketones/therapeutic use* ; Mice ; Mice, SCID ; Oncolytic Viruses/drug effects* ; Oncolytic Viruses/pathogenicity ; Reoviridae/drug effects* ; Reoviridae/pathogenicity ; Reoviridae/physiology ; Reoviridae Infections/therapy* ; Virus Replication/drug effects
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
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
Yonsei Authors
Yun, Chae Ok(윤채옥)
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