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      Anti-Enterovirus 71 Effects of Chrysin and Its Phosphate Ester

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          Abstract

          Enterovirus 71 (EV71) can cause severe disease and even lead to death in children, and an effective antiviral drug is currently unavailable. The anti-EV71 effect of chrysin (5,7-dihydroxyflavone), a natural flavonoid commonly found in many plants, was tested in this report. By using the predicting program Autodock 4.0 and an in vitro protease inhibition assay, we found that chrysin could suppress viral 3C pro activity. Replication of viral RNA and production of viral capsid protein and the infectious virion were strongly inhibited by chrysin, without noticeable cytotoxicity. Cytopathic effects on cells were also prevented. Diisopropyl chrysin-7-yl phosphate (CPI), the phosphate ester for chrysin, was generated through a simplified Atheron-Todd reaction to achieve stronger anti-viral activity. CPI was also able to bind with and inhibit viral 3C pro activity in vitro. As expected, CPI demonstrated more potent antiviral activity against EV71.

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          Most cited references 38

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          Scavenger receptor B2 is a cellular receptor for enterovirus 71.

          Enterovirus 71 (EV71) belongs to human enterovirus species A of the genus Enterovirus within the family Picornaviridae. EV71, together with coxsackievirus A16 (CVA16), are most frequently associated with hand, foot and mouth disease (HFMD). Although HFMD is considered a mild exanthematous infection, infections involving EV71, but not CVA16, can progress to severe neurological disease, including fatal encephalitis, aseptic meningitis and acute flaccid paralysis. In recent years, epidemic and sporadic outbreaks of neurovirulent EV71 infections have been reported in Taiwan, Malaysia, Singapore, Japan and China. Here, we show that human scavenger receptor class B, member 2 (SCARB2, also known as lysosomal integral membrane protein II or CD36b like-2) is a receptor for EV71. EV71 binds soluble SCARB2 or cells expressing SCARB2, and the binding is inhibited by an antibody to SCARB2. Expression of human SCARB2 enables normally unsusceptible cell lines to support EV71 propagation and develop cytopathic effects. EV71 infection is hampered by the antibody to SCARB2 and soluble SCARB2. SCARB2 also supports the infection of the milder pathogen CVA16. The identification of SCARB2 as an EV71 and CVA16 receptor contributes to a better understanding of the pathogenicity of these viruses.
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            Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71.

            Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease (HFMD), a common febrile disease occurring mainly in young children. Although clinical manifestations of HFMD are usually mild and self limiting, a severe EV71 outbreak can lead to a diverse array of neurological diseases. Identification of the specific cellular receptors is crucial for elucidating the mechanism of early virus-host interactions and the pathogenesis of enteroviruses. Here we identify human P-selectin glycoprotein ligand-1 (PSGL-1; CD162), a sialomucin membrane protein expressed on leukocytes that has a major role in early stages of inflammation, as a functional receptor for EV71 using an expression cloning method by panning. The N-terminal region of PSGL-1 binds specifically to EV71. Stable PSGL-1 expression allowed EV71 entry and replication, and development of cytopathic effects in nonsusceptible mouse L929 cells. Five out of eight EV71 strains bound soluble PSGL-1 and used intact PSGL-1 as the primary receptor for infection of Jurkat T cells. Three other EV71 strains did not use PSGL-1, suggesting the presence of strain-specific replication of EV71 in leukocytes. EV71 replicated in nonleukocyte cell lines in a PSGL-1-independent manner, indicating the presence of alternative receptor(s) for EV71. The identification of PSGL-1 as a receptor for EV71 sheds new light on a role for PSGL-1-positive leukocytes in cell tropism and pathogenesis during the course of HFMD and other EV71-mediated diseases.
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              Neurological manifestations of enterovirus 71 infection in children during an outbreak of hand, foot, and mouth disease in Western Australia.

              Enterovirus 71 (EV71) causes epidemics of hand, foot, and mouth disease associated with neurological complications in young children. We report an outbreak of EV71-associated neurological disease that occurred from February through September 1999 in Perth, Western Australia. Fourteen children with culture-proven, EV71-induced neurological disease were identified. Nine patients (64%) developed severe neurological disease; 4 of these patients developed long-term neurological sequelae. Neurological syndromes included aseptic meningitis, Guillain-Barré syndrome, acute transverse myelitis, acute cerebellar ataxia, opso-myoclonus syndrome, benign intracranial hypertension, and a febrile convulsion. Clinical and magnetic resonance imaging data indicated that immunopathology was a major factor in the pathogenesis of neurological disease in this outbreak. This finding is in contrast to reports of previous EV71 epidemics, in which virus-induced damage to gray matter was the most frequent cause of neurological disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                5 March 2014
                : 9
                : 3
                Affiliations
                MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
                University of North Carolina School of Medicine, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JW TZ. Performed the experiments: JW TZ JD. Analyzed the data: JW TZ JD SC FY QJ. Contributed reagents/materials/analysis tools: JW TZ JD SC. Wrote the paper: JW TZ JD SC FY QJ.

                Article
                PONE-D-13-47489
                10.1371/journal.pone.0089668
                3943725
                24598537

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 9
                Funding
                The work was supported by the National Science and Technology Major Project of China, project No.2013ZX10004-601, No.2011ZX10004-001 and No.2013ZX10004-101. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biochemistry
                Biochemistry Simulations
                Computational Biology
                Biochemical Simulations
                Microbiology
                Virology
                Antivirals
                Emerging Viral Diseases
                Chemistry
                Phytochemistry
                Phytochemicals
                Medicine
                Infectious Diseases
                Viral Diseases
                Enterovirus Infection

                Uncategorized

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