Inhibition of Reovirus by Mycophenolic Acid Is Associated with the M1 Genome Segment

Hermann, Laura; Coombs, Kevin M.

doi:10.1128/jvi.78.12.6171-6179.2004

Cited by 21 publications

(20 citation statements)

References 69 publications

(75 reference statements)

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“…Mycophenolic acid is an orally available immunosuppressant used for prevention of posttransplant organ rejection. Mycophenolic acid has activity against many RNA and DNA viruses (4,9,16,22,23,29,35,43), including poxviruses (9,19,49). Its antiviral activity is linked to inhibition of purine metabolism, insofar as virus replication is rescued by exogenous guanosine.…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Antipoxviral Agents: Mitoxantrone Inhibits Vaccinia Virus Replication by Blocking Virion Assembly

Deng¹,

Dai

Ciro

et al. 2007

J Virol

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The bioterror threat of a smallpox outbreak in an unvaccinated population has mobilized efforts to develop new antipoxviral agents. By screening a library of known drugs, we identified 13 compounds that inhibited vaccinia virus replication at noncytotoxic doses. The anticancer drug mitoxantrone is unique among the inhibitors identified in that it has no apparent impact on viral gene expression. Rather, it blocks processing of viral structural proteins and assembly of mature progeny virions. The isolation of mitoxantrone-resistant vaccinia strains underscores that a viral protein is the likely target of the drug. Whole-genome sequencing of mitoxantrone-resistant viruses pinpointed missense mutations in the N-terminal domain of vaccinia DNA ligase. Despite its favorable activity in cell culture, mitoxantrone administered intraperitoneally at the maximum tolerated dose failed to protect mice against a lethal intranasal infection with vaccinia virus.Poxviruses have been at the forefront of advances in medicine for 200 years, from Jenner's paper on the efficacy of vaccination against smallpox in 1798 to the successful use of vaccinia virus to eradicate human smallpox disease, as proclaimed by the World Health Organization in 1977. Throughout the 1990s, the scientific community debated the proposed destruction of the last known stocks of smallpox virus (24, 31). Hanging over this discussion was the fear that undeclared stocks of smallpox could be used as a bioterror weapon against an unvaccinated population. The urgency of this threat was amplified by the terrorist attacks of 2001, followed by the dissemination of anthrax via the postal service. The outbreak of human monkeypox infections in the United States in 2003 further highlighted the risks of reemergence of human poxvirus disease.Public health and research efforts have been mobilized accordingly to (i) exploit a modified live smallpox vaccine that maintains efficacy while minimizing complications, (ii) pursue alternatives to live vaccination for smallpox prophylaxis, and (iii) discover and bring forward for FDA approval new antipoxviral drugs. Two very different clinical scenarios present different challenges for drug therapy. Prophylaxis of a low-risk population in the event of a threat or actual outbreak mandates an orally available drug with minimal side effects. In contrast, the treatment of confirmed cases of smallpox (which can have a Ն30% fatality rate) need not be hindered by concerns about route of administration and non-life-threatening side effects. The goal is to have at least two approved antipoxviral drugs that act on different molecular targets.Although many inhibitors of poxvirus replication in culture or animal models have been described previously (50), the initial efforts post-2001 focused on the nucleoside analog cidofovir, an inhibitor of the viral DNA polymerase (28), which was already FDA approved for treatment of cytomegalovirus retinitis. Cidofovir was found to be effective in animal models of orthopoxvirus infection (37,50,53). However,...

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Section: Resultsmentioning

confidence: 99%

Identification of Novel Antipoxviral Agents: Mitoxantrone Inhibits Vaccinia Virus Replication by Blocking Virion Assembly

Deng¹,

Dai

Ciro

et al. 2007

J Virol

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“…Gallate derivatives that display antiviral effects are used as antioxidant food additives, including EÀ310 (propyl gallate), EÀ311 (octyl gallate), and EÀ312 (lauryl gallate) (39). Mycophenolic acid has additionally been identified as an anti-reoviral agent, acting as a reversible inhibitor of eukaryotic IMP dehydrogenase (IMPDH) (40). Another study demonstrated that chestnut and quebracho wood extracts containing tannin show antiviral activity against avian reovirus and metapneumovirus (41).…”

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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“…However, in normal cells, viral infection triggers PKR phosphorylation, which in turn leads to inhibition of viral gene translation, cell apoptosis and termination of viral infection. Apart from the natural mechanism present in non-neoplastic cells, reovirus infection can be contained by mycophenolic acid, an immunosuppressive agent [28]. The major disadvantage of this oncolytic vector is its nonalterable ten segments of genome, which renders this virus impossible to engineer for specific mutations [29].…”

Section: History Of Oncolytic Virotherapymentioning

confidence: 99%

Antiglioma Oncolytic Virotherapy: Unattainable Goal or a Success Story in the Making?

et al. 2013

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Initial observations from as early as the mid-1800s suggested that patients suffering from hematological malignancies would transiently go into remission upon naturally contracting viral infections laid the foundation for the oncolytic virotherapy research field. Since then, research focusing on anticancer oncolytic virotherapy has rapidly evolved. Today, oncolytic viral vectors have been engineered to stimulate and manipulate the host immune system, selectively targeting tumor tissues while sparing non-neoplastic cells. Glioblastoma multiforme, the most common adult primary brain tumor, has a disasterous history. It is one of the most deadly cancers known to humankind. Over the last century our understanding of this disease has grown exponentially. However, the median survival of patients suffering from this disease has only been extended by a few months. Even with the best, most aggressive modern therapeutic approaches available, malignant gliomas are still virtually 100% fatal. Motivated by the desperate need to find effective treatment strategies, more investments have been applied to oncolytic virotherapy preclinical and clinical studies. In this review we will discuss the antiglioma oncolytic virotherapy research field. We will survey its history and the principles laid down to serve as basis for preclinical works. We will also debate the variety of viral vectors used, their clinical applications, the lessons learned from clinical trials and possible future directions.

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Inhibition of Reovirus by Mycophenolic Acid Is Associated with the M1 Genome Segment

Cited by 21 publications

References 69 publications

Identification of Novel Antipoxviral Agents: Mitoxantrone Inhibits Vaccinia Virus Replication by Blocking Virion Assembly

Identification of Novel Antipoxviral Agents: Mitoxantrone Inhibits Vaccinia Virus Replication by Blocking Virion Assembly

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

Antiglioma Oncolytic Virotherapy: Unattainable Goal or a Success Story in the Making?

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