Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo
Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne flaviviruses that cause severe illness after infection. Currently, there are no specific or effective treatments against DENV and ZIKV. Previous studies have shown that tyrosine kinase activities and signal transduction are involved in fla...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/11/4050 |
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| author | Fu-Kai Chuang Ching-Len Liao Ming-Kuan Hu Yi-Lin Chiu An-Rong Lee Shih-Ming Huang Yu-Lung Chiu Pei-Ling Tsai Bo-Cyuan Su Tsung-Hsien Chang Chang-Chi Lin Chih-Chin Shih Li-Chen Yen |
| author_facet | Fu-Kai Chuang Ching-Len Liao Ming-Kuan Hu Yi-Lin Chiu An-Rong Lee Shih-Ming Huang Yu-Lung Chiu Pei-Ling Tsai Bo-Cyuan Su Tsung-Hsien Chang Chang-Chi Lin Chih-Chin Shih Li-Chen Yen |
| author_sort | Fu-Kai Chuang |
| collection | DOAJ |
| description | Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne flaviviruses that cause severe illness after infection. Currently, there are no specific or effective treatments against DENV and ZIKV. Previous studies have shown that tyrosine kinase activities and signal transduction are involved in flavivirus replication, suggesting a potential therapeutic strategy for DENV and ZIKV. In this study, we found that compound <b>L3</b> can significantly reduce viral protein expression and viral titers in HEK-293, MCF-7, HepG2, and Huh-7 cells and exhibits superior therapeutic efficacy against flaviviral infection compared to other tyrosine kinase inhibitors. In addition, compound <b>L3</b> can decrease endogenous HER2 activation and inhibit the phosphorylation of the HER2 downstream signaling molecules Src and ERK1/2, the levels of which have been associated with viral protein expression in MCF-7 cells. Moreover, silencing HER2 diminished DENV-2 and ZIKV expression in MCF-7 cells, which suggests that HER2 activity is involved in flavivirus replication. Furthermore, in DENV-2-infected AG129 mice, treatment with compound <b>L3</b> increased the survival rates and reduced the viremia levels. Overall, compound <b>L3</b> demonstrates therapeutic efficacy both in vitro and in vivo and could be developed as a promising antiviral drug against emerging flaviviruses or for concurrent DENV and ZIKV outbreaks. |
| first_indexed | 2024-03-10T19:21:22Z |
| format | Article |
| id | doaj.art-ed3c9f43b1a945148757c780df896afe |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T19:21:22Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ed3c9f43b1a945148757c780df896afe2023-11-20T02:58:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-06-012111405010.3390/ijms21114050Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In VivoFu-Kai Chuang0Ching-Len Liao1Ming-Kuan Hu2Yi-Lin Chiu3An-Rong Lee4Shih-Ming Huang5Yu-Lung Chiu6Pei-Ling Tsai7Bo-Cyuan Su8Tsung-Hsien Chang9Chang-Chi Lin10Chih-Chin Shih11Li-Chen Yen12Penghu Branch of Tri-Service General Hospital, Penghu 88056, TaiwanDepartment of Microbiology and Immunology, National Defense Medical Center, 161, Sec. 6, Min-Chuan E. Road, Neihu, Taipei 11490, TaiwanSchool of Pharmacy, National Defense Medical Center, Taipei 11490, TaiwanDepartment of Biochemistry, National Defense Medical Center, Taipei 11490, TaiwanSchool of Pharmacy, National Defense Medical Center, Taipei 11490, TaiwanDepartment of Biochemistry, National Defense Medical Center, Taipei 11490, TaiwanSchool of Public Health, National Defense Medical Center, Taipei 11490, TaiwanDepartment of Microbiology and Immunology, National Defense Medical Center, 161, Sec. 6, Min-Chuan E. Road, Neihu, Taipei 11490, TaiwanDepartment of Microbiology and Immunology, National Defense Medical Center, 161, Sec. 6, Min-Chuan E. Road, Neihu, Taipei 11490, TaiwanDepartment of Microbiology and Immunology, National Defense Medical Center, 161, Sec. 6, Min-Chuan E. Road, Neihu, Taipei 11490, TaiwanDepartment of Microbiology and Immunology, National Defense Medical Center, 161, Sec. 6, Min-Chuan E. Road, Neihu, Taipei 11490, TaiwanDepartment of Pharmacology, National Defense Medical Center, Taipei 11490, TaiwanDepartment of Microbiology and Immunology, National Defense Medical Center, 161, Sec. 6, Min-Chuan E. Road, Neihu, Taipei 11490, TaiwanDengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne flaviviruses that cause severe illness after infection. Currently, there are no specific or effective treatments against DENV and ZIKV. Previous studies have shown that tyrosine kinase activities and signal transduction are involved in flavivirus replication, suggesting a potential therapeutic strategy for DENV and ZIKV. In this study, we found that compound <b>L3</b> can significantly reduce viral protein expression and viral titers in HEK-293, MCF-7, HepG2, and Huh-7 cells and exhibits superior therapeutic efficacy against flaviviral infection compared to other tyrosine kinase inhibitors. In addition, compound <b>L3</b> can decrease endogenous HER2 activation and inhibit the phosphorylation of the HER2 downstream signaling molecules Src and ERK1/2, the levels of which have been associated with viral protein expression in MCF-7 cells. Moreover, silencing HER2 diminished DENV-2 and ZIKV expression in MCF-7 cells, which suggests that HER2 activity is involved in flavivirus replication. Furthermore, in DENV-2-infected AG129 mice, treatment with compound <b>L3</b> increased the survival rates and reduced the viremia levels. Overall, compound <b>L3</b> demonstrates therapeutic efficacy both in vitro and in vivo and could be developed as a promising antiviral drug against emerging flaviviruses or for concurrent DENV and ZIKV outbreaks.https://www.mdpi.com/1422-0067/21/11/4050flavivirusdengue virusZika virusanti-viral drugstyrosine kinase inhibitors |
| spellingShingle | Fu-Kai Chuang Ching-Len Liao Ming-Kuan Hu Yi-Lin Chiu An-Rong Lee Shih-Ming Huang Yu-Lung Chiu Pei-Ling Tsai Bo-Cyuan Su Tsung-Hsien Chang Chang-Chi Lin Chih-Chin Shih Li-Chen Yen Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo International Journal of Molecular Sciences flavivirus dengue virus Zika virus anti-viral drugs tyrosine kinase inhibitors |
| title | Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo |
| title_full | Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo |
| title_fullStr | Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo |
| title_full_unstemmed | Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo |
| title_short | Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo |
| title_sort | antiviral activity of compound l3 against dengue and zika viruses in vitro and in vivo |
| topic | flavivirus dengue virus Zika virus anti-viral drugs tyrosine kinase inhibitors |
| url | https://www.mdpi.com/1422-0067/21/11/4050 |
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