Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptors

Chung Fan Hsieh, Jia Rong Jheng, Guan Hua Lin, Yu Li Chen, Jin Yuan Ho, Chien Jou Liu, Kuei Yang Hsu, Yuan Siao Chen, Yoke Fun Chan, Hui Ming Yu, Pei Wen Hsieh, Jyh Haur Chern*, Jim Tong Horng*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

41 Scopus citations

Abstract

Enterovirus A71 (EV-A71), a positive-stranded RNA virus of the Picornaviridae family, may cause neurological complications or fatality in children. We examined specific factors responsible for this virulence using a chemical genetics approach. Known compounds from an anti-EV-A71 herbal medicine, Salvia miltiorrhiza (Danshen), were screened for anti-EV-A71. We identified a natural product, rosmarinic acid (RA), as a potential inhibitor of EV-A71 by cell-based antiviral assay and in vivo mouse model. Results also show that RA may affect the early stage of viral infection and may target viral particles directly, thereby interfering with virus-P-selectin glycoprotein ligand-1 (PSGL1) and virus-heparan sulfate interactions without abolishing the interaction between the virus and scavenger receptor B2 (SCARB2). Sequencing of the plaque-purified RA-resistant viruses revealed a N104K mutation in the five-fold axis of the structural protein VP1, which contains positively charged amino acids reportedly associated with virus-PSGL1 and virus-heparan sulfate interactions via electrostatic attraction. The plasmid-derived recombinant virus harbouring this mutation was confirmed to be refractory to RA inhibition. Receptor pull-down showed that this non-positively charged VP1-N104 is critical for virus binding to heparan sulfate. As the VP1-N104 residue is conserved among different EV-A71 strains, RA may be useful for inhibiting EV-A71 infection, even for emergent virus variants. Our study provides insight into the molecular mechanism of virus-host interactions and identifies a promising new class of inhibitors based on its antiviral activity and broad spectrum effects against a range of EV-A71.

Original languageEnglish
Pages (from-to)1194-1205
Number of pages12
JournalEmerging Microbes and Infections
Volume9
Issue number1
DOIs
StatePublished - 01 01 2020

Bibliographical note

Publisher Copyright:
© 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd.

Keywords

  • Enterovirus A71
  • P-selectin glycoprotein ligand-1
  • five-fold axis
  • heparan sulfate
  • receptor
  • rosmarinic acid
  • scavenger receptor B2
  • viral entry

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