Please use this identifier to cite or link to this item: https://doi.org/10.1126/scitranslmed.aar5759
Title: Prunin suppresses viral IRES activity and is a potential candidate for treating enterovirus A71 infection
Authors: Gunaseelan, Saravanan
Wong, Kai Zhi
Min, Nyo
Sun, Jialei
Ismail, Nur Khairiah Binte Mohd
Tan, Yee Joo 
Lee, Regina Ching Hua
Chu, Justin Jang Hann 
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
RIBOSOME ENTRY SITE
RNA-BINDING PROTEIN
FAMILY TYROSINE KINASES
HEPATITIS-C
ANTIVIRAL ACTIVITY
MESSENGER-RNA
MAMMALIAN-CELLS
IN-VITRO
COMBINATION THERAPY
LETHAL MUTAGENESIS
Issue Date: 30-Oct-2019
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Citation: Gunaseelan, Saravanan, Wong, Kai Zhi, Min, Nyo, Sun, Jialei, Ismail, Nur Khairiah Binte Mohd, Tan, Yee Joo, Lee, Regina Ching Hua, Chu, Justin Jang Hann (2019-10-30). Prunin suppresses viral IRES activity and is a potential candidate for treating enterovirus A71 infection. SCIENCE TRANSLATIONAL MEDICINE 11 (516). ScholarBank@NUS Repository. https://doi.org/10.1126/scitranslmed.aar5759
Abstract: © 2019 The Authors. Human enterovirus A71 (HEVA71) causes hand, foot, and mouth disease (HFMD) in young children and is considered a major neurotropic pathogen but lacks effective antivirals. To identify potential therapeutic agents against HFMD, we screened a 502-compound flavonoid library for compounds targeting the HEVA71 internal ribosome entry site (IRES) that facilitates translation of the HEVA71 genome and is vital for the production of HEVA71 viral particles. We validated hits using cell viability and viral plaque assays and found that prunin was the most potent inhibitor of HEVA71. Downstream assays affirmed that prunin disrupted viral protein and RNA synthesis and acted as a narrow-spectrum antiviral against enteroviruses A and B, but not enterovirus C, rhinovirus A, herpes simplex 1, or chikungunya virus. Continuous HEVA71 passaging with prunin yielded HEVA71-resistant mutants with five mutations that mapped to the viral IRES. Knockdown studies showed that the mutations allowed HEVA71 to overcome treatment-induced suppression by differentially regulating recruitment of the IRES trans-acting factors Sam68 and hnRNPK without affecting the hnRNPA1-IRES interaction required for IRES translation. Furthermore, prunin effectively reduced HEVA71-associated clinical symptoms and mortality in HEVA71-infected BALB/c mice and suppressed hepatitis C virus at higher concentrations, suggesting a similar mechanism of prunin-mediated IRES inhibition for both viruses. These studies establish prunin as a candidate for further development as a HEVA71 therapeutic agent.
Source Title: SCIENCE TRANSLATIONAL MEDICINE
URI: https://scholarbank.nus.edu.sg/handle/10635/173277
ISSN: 19466234
19466242
DOI: 10.1126/scitranslmed.aar5759
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