Soluble Coxsackievirus B3 3C Protease Inhibitor Prevents Cardiomyopathy in an Experimental Chronic Myocarditis Murine Model

Lim, Byung-Kwan; Yun, Sangwoon; Ju, Eun-Seon; Kim, Bokyoung; Lee, You-Jung; Yoo, Dongkyeom; Kim, Young‐Chul; Jeon, Eun‐Seok

doi:10.1016/j.virusres.2014.11.030

Cited by 19 publications

(22 citation statements)

References 18 publications

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“…A case series of 13 patients with severe refractory adenovirus infections, although not including myocarditis, treated with CMX001 reported nearly 70 % of patients had a substantial decrease in detectable adenovirus DNA and had significantly improved survival compared to non-responders [9]. In murine models of coxsackievirus myocarditis, an experimental 3C pro-tease inhibitor reduced myocardial damage and mortality [17] as well as the development of the DCM phenotype after infection [12]. While these results are promising, whether virus-specific therapy in children with myocarditis can affect viral clearance and clinical outcomes remains unknown.…”

Section: Discussionmentioning

confidence: 99%

High Frequency of Detection by PCR of Viral Nucleic Acid in The Blood of Infants Presenting with Clinical Myocarditis

et al. 2015

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Specific viruses are associated with pediatric myocarditis, but the prevalence of viral DNAemia detected by blood polymerase chain reaction (PCR) is unknown. We evaluated the prevalence of known cardiotropic viruses (enterovirus, adenovirus, human herpesvirus 6, and parvovirus B19) in children with clinical myocarditis (n = 21). Results were compared to pediatric controls with similar viral PCR testing. The majority of positive PCR (89 %) was noted in children ≤12 months of age at diagnosis compared to older children. Infant myocarditis patients (8/10) had increased the prevalence of PCR positivity compared to infant pediatric controls (4/114) (p < 0.0001). Other than age, patient characteristics at diagnosis were similar between PCR-positive and PCR-negative patients. Both PCR-negative myocarditis infants had clinical recovery at follow-up. Of the PCR-positive myocarditis infants, 4 had clinical recovery, 2 developed chronic cardiomyopathy, 1 underwent heart transplant, and 1 died. Infants with clinical myocarditis have a high rate of blood viral positivity, which is higher compared to older children with myocarditis and healthy infant controls. Age-related differences in PCR positivity may be due to differences in host and/or virus characteristics. Our findings suggest that viral blood PCR may be a useful diagnostic tool and identify patients who would potentially benefit from virus-specific therapy.

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Section: Discussionmentioning

confidence: 99%

High Frequency of Detection by PCR of Viral Nucleic Acid in The Blood of Infants Presenting with Clinical Myocarditis

et al. 2015

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“…The chemical modification from water-insolubility to water-solubility shows a positive effect. Indeed, water-insoluble 3C pro inhibitors of CV B3 dissolved in 100% dimethyl sulfoxide (DMSO) have been reported to inhibit viral proliferation and to decrease myocardial damage and mortality in a chronic myocarditis model [ 137 , 138 ]. With the exception of organic solvents, organic reagents exhibit potential as 3C pro inhibitors.…”

Section: Treatmentmentioning

confidence: 99%

Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Sun

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Cheng

et al. 2016

Viruses

105

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The Picornaviridae family comprises a large group of non-enveloped viruses that have a major impact on human and veterinary health. The viral genome contains one open reading frame encoding a single polyprotein that can be processed by viral proteinases. The crucial 3C proteinases (3Cpros) of picornaviruses share similar spatial structures and it is becoming apparent that 3Cpro plays a significant role in the viral life cycle and virus host interaction. Importantly, the proteinase and RNA-binding activity of 3Cpro are involved in viral polyprotein processing and the initiation of viral RNA synthesis. In addition, 3Cpro can induce the cleavage of certain cellular factors required for transcription, translation and nucleocytoplasmic trafficking to modulate cell physiology for viral replication. Due to interactions between 3Cpro and these essential factors, 3Cpro is also involved in viral pathogenesis to support efficient infection. Furthermore, based on the structural conservation, the development of irreversible inhibitors and discovery of non-covalent inhibitors for 3Cpro are ongoing and a better understanding of the roles played by 3Cpro may provide insights into the development of potential antiviral treatments. In this review, the current knowledge regarding the structural features, multiple functions in the viral life cycle, pathogen host interaction, and development of antiviral compounds for 3Cpro is summarized.

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“…The design of inhibitors against CVB proteases might provide an opportunity to limit viral replication and reduce virus-associated pathology. A soluble inhibitor of CVB 3C protease was shown to prevent cardiomyopathy following infection (Lim, Yun et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Recent progress in understanding coxsackievirus replication, dissemination, and pathogenesis

et al. 2015

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Coxsackieviruses (CVs) are relatively common viruses associated with a number of serious human diseases, including myocarditis and meningo-encephalitis. These viruses are considered cytolytic yet can persist for extended periods of time within certain host tissues requiring evasion from the host immune response and a greatly reduced rate of replication. A member of Picornaviridae family, CVs have been historically considered non-enveloped viruses – although recent evidence suggest that CV and other picornaviruses hijack host membranes and acquire an envelope. Acquisition of an envelope might provide distinct benefits to CV virions, such as resistance to neutralizing antibodies and efficient nonlytic viral spread. CV exhibits a unique tropism for progenitor cells in the host which may help to explain the susceptibility of the young host to infection and the establishment of chronic disease in adults. CVs have also been shown to exploit autophagy to maximize viral replication and assist in unconventional release from target cells. In this article, we review recent progress in clarifying virus replication and dissemination within the host cell, identifying determinants of tropism, and defining strategies utilized by the virus to evade the host immune response. Also, we will highlight unanswered questions and provide future perspectives regarding the potential mechanisms of CV pathogenesis.

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Soluble Coxsackievirus B3 3C Protease Inhibitor Prevents Cardiomyopathy in an Experimental Chronic Myocarditis Murine Model

Abstract: Water soluble 3CPI was delivered through i.p. injection after CVB3 infection. This agent preserved heart function and decreased organ viral titers and myocardial damage. Soluble 3CPI may be beneficial in the treatment of cardiomyopathy associated with enterovirus infection.

Cited by 19 publications

References 18 publications

High Frequency of Detection by PCR of Viral Nucleic Acid in The Blood of Infants Presenting with Clinical Myocarditis

High Frequency of Detection by PCR of Viral Nucleic Acid in The Blood of Infants Presenting with Clinical Myocarditis

Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Recent progress in understanding coxsackievirus replication, dissemination, and pathogenesis

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