Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptors
ABSTRACTEnterovirus 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 medic...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | Emerging Microbes and Infections |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2020.1767512 |
| _version_ | 1797265891316989952 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Chung-Fan Hsieh |
| collection | DOAJ |
| description | ABSTRACTEnterovirus 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. |
| first_indexed | 2024-03-07T17:24:18Z |
| format | Article |
| id | doaj.art-b45d4f4b770747599437838685b96c2c |
| institution | Directory Open Access Journal |
| issn | 2222-1751 |
| language | English |
| last_indexed | 2024-04-25T00:52:00Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
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| series | Emerging Microbes and Infections |
| spelling | doaj.art-b45d4f4b770747599437838685b96c2c2024-03-11T16:04:24ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512020-01-01911194120510.1080/22221751.2020.1767512Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptorsChung-Fan Hsieh0Jia-Rong Jheng1Guan-Hua Lin2Yu-Li Chen3Jin-Yuan Ho4Chien-Jou Liu5Kuei-Yang Hsu6Yuan-Siao Chen7Yoke Fun Chan8Hui-Ming Yu9Pei-Wen Hsieh10Jyh-Haur Chern11Jim-Tong Horng12Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, TaiwanDepartment of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, TaiwanDepartment of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, TaiwanDepartment of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, TaiwanDepartment of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, TaiwanDepartment of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, TaiwanDepartment of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, TaiwanGenomics Research Center, Academia Sinica, Taipei, TaiwanDepartment of Medical Microbiology, University Malaya, Kuala Lumpur, MalaysiaGenomics Research Center, Academia Sinica, Taipei, TaiwanGraduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan, ROCDepartment of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, TaiwanABSTRACTEnterovirus 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.https://www.tandfonline.com/doi/10.1080/22221751.2020.1767512Enterovirus A71five-fold axisheparan sulfateP-selectin glycoprotein ligand-1receptorrosmarinic acid |
| spellingShingle | 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 Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptors Emerging Microbes and Infections Enterovirus A71 five-fold axis heparan sulfate P-selectin glycoprotein ligand-1 receptor rosmarinic acid |
| title | Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptors |
| title_full | Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptors |
| title_fullStr | Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptors |
| title_full_unstemmed | Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptors |
| title_short | Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptors |
| title_sort | rosmarinic acid exhibits broad anti enterovirus a71 activity by inhibiting the interaction between the five fold axis of capsid vp1 and cognate sulfated receptors |
| topic | Enterovirus A71 five-fold axis heparan sulfate P-selectin glycoprotein ligand-1 receptor rosmarinic acid |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2020.1767512 |
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