Z-FA-FMK as a novel potent inhibitor of reovirus pathogenesis and oncolysis in vivo.
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.
Kim
Manbok
M
Department of Biochemistry and Molecular Biology, University of Calgary, AB, Canada.
Hansen
Kristina K
KK
Davis
Lesley
L
van Marle
Guido
G
Gill
Michael John
MJ
Fox
Julie D
JD
Hollenberg
Morley D
MD
Rancourt
Derrick E
DE
Lee
Patrick W K
PW
Yun
Chae-Ok
CO
Johnston
Randal N
RN
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D002213:Capsid / Q000187:drug effects / Q000502:physiology / Q000821:virology; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D004151:Dipeptides / Q000627:therapeutic use*; D011905:Genes, ras; D006801:Humans; D007659:Ketones / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D050504:Oncolytic Viruses / Q000187:drug effects* / Q000472:pathogenicity; D012087:Reoviridae / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D012088:Reoviridae Infections / Q000628:therapy*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D007659:Ketones; C057383:MDL 201053