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

Kim, Manbok; Hansen, Kristina K.; Davis, Lesley; Marle, Guido van; Gill, M. John; Fox, Julie D.; Hollenberg, Morley D.; Rancourt, Derrick E.; Lee, Patrick W.K.; Yun, Chae Ok; Johnston, Randal N.

doi:10.3851/imp1646

Cited by 14 publications

(6 citation statements)

References 28 publications

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“…Another study demonstrated that chestnut and quebracho wood extracts containing tannin show antiviral activity against avian reovirus and metapneumovirus (41). The dipeptide, benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone (Z-FA-FMK), is a novel potent inhibitor of reovirus pathogenesis and oncolysis in vivo (42). These drugs act by inhibiting reovirus replication and adsorption, but their potential side-effects are yet to be clinically evaluated.…”

Section: Discussionmentioning

confidence: 99%

In vitro anti-reovirus activity of kuraridin isolated from Sophora flavescens against viral replication and hemagglutination

Kwon

Jeong

Lee

et al. 2015

Journal of Pharmacological Sciences

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In this study, we evaluated the anti-reovirus activity of kuraridin isolated from the roots of Sophora flavescens. In particular, we focused on whether this property is attributable to direct inhibition of reovirus attachment and/or inhibition of viral replication with the aid of time-of-addition (pre-treatment, simultaneous treatment, and post-treatment) experiments. No significant antiviral activity of kuraridin was detected in the pre-treatment assay. In the simultaneous assay, the 50% effective inhibitory concentrations (EC50) of kuraridin were 15.3-176.9 μM against human type 1-3 reoviruses (HRV1-3) and Korean porcine reovirus (PRV). Kuraridin completely blocked binding of viral sigma 1 protein to sialic acids at concentrations lower than 82.5 μM in the hemagglutination inhibition assay. Moreover, kuraridin inhibited HRV1-3 and PRV viral replication with EC50 values of 14.0-62.0 μM. Quantitative real-time PCR analysis disclosed strong suppression of reovirus RNA synthesis at the late stage (18 h) of virus replication by kuraridin. The viral yields of kuraridin-treated cells were significantly reduced at 24 h post-infection, compared with DMSO-treated cells. Our results collectively suggest that kuraridin inhibits virus adsorption and replication by inhibiting hemagglutination, viral RNA and protein synthesis and virus shedding, supporting its utility as a viable candidate antiviral drug against reoviruses.

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Section: Discussionmentioning

confidence: 99%

In vitro anti-reovirus activity of kuraridin isolated from Sophora flavescens against viral replication and hemagglutination

Kwon

Jeong

Lee

et al. 2015

Journal of Pharmacological Sciences

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“…Reovirusinduced myocarditis is not immune-mediated, and infection will cause myocarditic lesions in nude mice or mice lacking B-and T-cells [47,76]. Reovirus-induced cardiac damage occurs as a consequence virus-induced apoptosis of myocytes, and disease does not occur in mice lacking caspase 3 or in WT mice treated with inhibitors of apoptosis [77][78][79][80]. Comparisons of reovirus strains that vary in the capacity to cause myocarditis have identified phenotypic and genetic differences that correlate with myocarditic potential.…”

Section: Plos Pathogensmentioning

confidence: 99%

The multi-functional reovirus σ3 protein is a virulence factor that suppresses stress granule formation and is associated with myocardial injury

et al. 2021

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The mammalian orthoreovirus double-stranded (ds) RNA-binding protein σ3 is a multifunctional protein that promotes viral protein synthesis and facilitates viral entry and assembly. The dsRNA-binding capacity of σ3 correlates with its capacity to prevent dsRNA-mediated activation of protein kinase R (PKR). However, the effect of σ3 binding to dsRNA during viral infection is largely unknown. To identify functions of σ3 dsRNA-binding activity during reovirus infection, we engineered a panel of thirteen σ3 mutants and screened them for the capacity to bind dsRNA. Six mutants were defective in dsRNA binding, and mutations in these constructs cluster in a putative dsRNA-binding region on the surface of σ3. Two recombinant viruses expressing these σ3 dsRNA-binding mutants, K287T and R296T, display strikingly different phenotypes. In a cell-type dependent manner, K287T, but not R296T, replicates less efficiently than wild-type (WT) virus. In cells in which K287T virus demonstrates a replication deficit, PKR activation occurs and abundant stress granules (SGs) are formed at late times post-infection. In contrast, the R296T virus retains the capacity to suppress activation of PKR and does not mediate formation of SGs at late times post-infection. These findings indicate that σ3 inhibits PKR independently of its capacity to bind dsRNA. In infected mice, K287T produces lower viral titers in the spleen, liver, lungs, and heart relative to WT or R296T. Moreover, mice inoculated with WT or R296T viruses develop myocarditis, whereas those inoculated with K287T do not. Overall, our results indicate that σ3 functions to suppress PKR activation and subsequent SG formation during viral infection and that these functions correlate with virulence in mice.

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“…Reovirus-induced myocarditis is not immune-mediated, and infection will cause myocarditic lesions in nude mice or mice lacking B- and T-cells [42, 63]. Reovirus-induced cardiac damage occurs as a consequence virus-induced apoptosis of myocytes, and disease does not occur in mice lacking caspase 3 or in WT mice treated with inhibitors of apoptosis [64–67]. Comparisons of reovirus strains that vary in the capacity to cause myocarditis have identified phenotypic and genetic differences that correlate with myocarditic potential.…”

Section: Discussionmentioning

confidence: 99%

The multi-functional reovirus σ3 protein is a virulence factor that suppresses stress granule formation to allow viral replication and myocardial injury

Guo

Hinchman

Lewandrowski

et al. 2021

Preprint

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The mammalian orthoreovirus double-stranded (ds) RNA binding protein σ3 is a multifunctional protein that promotes viral protein synthesis and facilitates viral entry and assembly. The dsRNA-binding capacity of σ3 correlates with its capacity to prevent dsRNA-mediated activation of protein kinase R (PKR). However, the effect of σ3 binding to dsRNA during viral infection remains largely unknown. To identify functions of σ3 dsRNA-binding activity during reovirus infection, we engineered a panel of 13 σ3 mutants and screened them for the capacity to bind dsRNA. Six mutants were defective in dsRNA binding, and mutations in these constructs cluster in a putative dsRNA-binding region on the surface of σ3. Two recombinant viruses expressing these σ3 dsRNA-binding mutants, K287T and R296T, display strikingly different phenotypes. In a cell-type dependent manner, K287T, but not R296T, replicates less efficiently than wild-type (WT) virus. In cells in which K287T virus demonstrates a replication deficit, PKR activation occurs and abundant stress granules (SGs) are produced at late times post-infection. In contrast, the R296T virus retains the capacity to suppress activation of PKR and does not form SGs at late times post-infection. These findings indicate that σ3 inhibits PKR independently of its capacity to bind dsRNA. In infected mice, K287T produces lower viral titers in the spleen, liver, lungs, and heart relative to WT or R296T. Moreover, mice inoculated with WT or R296T viruses develop myocarditis, whereas those inoculated with K287T do not. Overall, our results indicate that σ3 functions to suppress PKR activation and subsequent SG formation during viral infection and that these functions correlate with virulence in mice.

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

Abstract: 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.

Cited by 14 publications

References 28 publications

In vitro anti-reovirus activity of kuraridin isolated from Sophora flavescens against viral replication and hemagglutination

In vitro anti-reovirus activity of kuraridin isolated from Sophora flavescens against viral replication and hemagglutination

The multi-functional reovirus σ3 protein is a virulence factor that suppresses stress granule formation and is associated with myocardial injury

The multi-functional reovirus σ3 protein is a virulence factor that suppresses stress granule formation to allow viral replication and myocardial injury

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