Vascular endothelial growth factor receptor 2 as a potential host target for the inhibition of enterovirus replication

Zhao, Xiaoyu1,2; Qiao, Rui2; Hao, Meng3; Xu, Longfa4; Wang, Dong5; Lu, Yinying1; Li, Jiayan2; Wu, Jing6; Li, Yi7; Cheng, Tong4; Zhang, Wenhong6; Zhao, Jincun5,8,9,10,11; Wang, Pengfei2

2024-09-01

10.1128/jvi.01129-24

JOURNAL OF VIROLOGY   影响因子和分区

0022-538X

1098-5514

["Because host kinases are key regulators of multiple signaling pathways in response to viral infections, we previously screened a kinase inhibitor library using rhabdomyosarcoma cells and human intestinal organoids in parallel to identify potent inhibitors against EV-A71 infection. We found that Rho-associated coiled-coil-containing protein kinase (Rock) inhibitor efficiently suppressed the EV-A71 replication and further revealed Rock1 as a novel EV-A71 host factor. In this study, subsequent analysis found that a variety of vascular endothelial growth factor receptor (VEGFR) inhibitors also had potent antiviral effects. Among the hits, Pazopanib, with a selectivity index as high as 254, which was even higher than that of Pirodavir, a potent broad-spectrum picornavirus inhibitor targeting viral capsid protein VP1, was selected for further analysis. We demonstrated that Pazopanib not only efficiently suppressed the replication of EV-A71 in a dose-dependent manner, but also exhibited broad-spectrum anti-enterovirus activity. Mechanistically, Pazopanib probably induces alterations in host cells, thereby impeding viral genome replication and transcription. Notably, VEGFR2 knockdown and overexpression suppressed and facilitated EV-A71 replication, respectively, indicating that VEGFR2 is a novel host dependency factor for EV-A71 replication. Transcriptome analysis further proved that VEGFR2 potentially plays a crucial role in combating EV-A71 infection through the TSAd-Src-PI3K-Akt pathway. These findings expand the range of potential antiviral candidates of anti-enterovirus therapeutics and suggest that VEGFR2 may be a key host factor involved in EV-A71 replication, making it a potential target for the development of anti-enterovirus therapeutics.IMPORTANCEAs the first clinical case was identified in the United States, EV-A71, a significant neurotropic enterovirus, has been a common cause of hand, foot, and mouth disease (HFMD) in infants and young children. Developing an effective antiviral agent for EV-A71 and other human enteroviruses is crucial, as these viral pathogens consistently cause outbreaks in humans. In this study, we demonstrated that multiple inhibitors against VEGFRs effectively reduced EV-A71 replication, with Pazopanib emerging as the top candidate. Furthermore, Pazopanib also attenuated the replication of other enteroviruses, including CVA10, CVB1, EV-D70, and HRV-A, displaying broad-spectrum anti-enterovirus activity. Given that Pazopanib targets various VEGFRs, we narrowed the focus to VEGFR2 using knockdown and overexpression experiments. Transcriptomic analysis suggests that Pazopanib's potential downstream targets involve the TSAd-Src-PI3K-Akt pathway. Our work may contribute to identifying targets for antiviral inhibitors and advancing treatments for human enterovirus infections.","As the first clinical case was identified in the United States, EV-A71, a significant neurotropic enterovirus, has been a common cause of hand, foot, and mouth disease (HFMD) in infants and young children. Developing an effective antiviral agent for EV-A71 and other human enteroviruses is crucial, as these viral pathogens consistently cause outbreaks in humans. In this study, we demonstrated that multiple inhibitors against VEGFRs effectively reduced EV-A71 replication, with Pazopanib emerging as the top candidate. Furthermore, Pazopanib also attenuated the replication of other enteroviruses, including CVA10, CVB1, EV-D70, and HRV-A, displaying broad-spectrum anti-enterovirus activity. Given that Pazopanib targets various VEGFRs, we narrowed the focus to VEGFR2 using knockdown and overexpression experiments. Transcriptomic analysis suggests that Pazopanib's potential downstream targets involve the TSAd-Src-PI3K-Akt pathway. Our work may contribute to identifying targets for antiviral inhibitors and advancing treatments for human enterovirus infections."]

EV-A71 kinase inhibitors VEGFR family VEGFR2 host factor

SCI

英语

通讯

MOST | National Key Research and Development Program of China (NKPs)["2023YFC2605400","2023YFC3404000"] ; National Key Research and Development Program of China["32300121","32300533","32270142"] ; National Natural Science Foundation of China[23PJD007] ; Shanghai Pujiang Programme[22QA1408800] ; Shanghai Rising-Star Program[23410760500] ; Program of Science and Technology Cooperation with Hong Kong, Macao and Taiwan[SKLGE-2304]

Virology

Virology

WOS:001313870500003

AMER SOC MICROBIOLOGY

Web of Science

1.Fudan Univ, Huashan Hosp, Inst Infect & Hlth, Shanghai Scitech Inno Ctr Infect & Immun,Natl Med, Shanghai, Peoples R China
2.Fudan Univ, Shanghai Pudong Hosp, Shanghai Inst Infect Dis & Biosecur, Sch Life Sci,Pudong Med Ctr,State Key Lab Genet En, Shanghai, Peoples R China
3.Fudan Univ, Greater Bay Area Inst Precis Med Guangzhou, Guangzhou, Peoples R China
4.Xiamen Univ, Sch Life Sci, State Key Lab Vaccines Infect Dis, Sch Publ Hlth,Xiang Biomed Lab, Xiamen, Peoples R China
5.Guangzhou Med Univ, Affiliated Hosp 1, Natl Clin Res Ctr Resp Dis, State Key Lab Resp Dis,Guangzhou Inst Resp Hlth, Guangzhou, Peoples R China
6.Fudan Univ, Huashan Hosp, Shanghai Med Coll, Natl Med Ctr Infect Dis,Shanghai Key Lab Infect Di, Shanghai, Peoples R China
7.Fudan Univ, Human Phenome Inst, Shanghai, Peoples R China
8.Guangzhou Lab, Bio Isl, Bio-Isl, Guangzhou, Peoples R China
9.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Sch Life Sci & Technol, Shanghai, Peoples R China
10.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Inst Hepatol, Sch Med,Natl Clin Res Ctr Infect Dis, Shenzhen, Peoples R China
11.Southern Univ Sci & Technol, Affiliated Hosp 2, Sch Med, Shenzhen, Peoples R China

Zhao, Xiaoyu,Qiao, Rui,Hao, Meng,et al. Vascular endothelial growth factor receptor 2 as a potential host target for the inhibition of enterovirus replication[J]. JOURNAL OF VIROLOGY,2024.

Zhao, Xiaoyu.,Qiao, Rui.,Hao, Meng.,Xu, Longfa.,Wang, Dong.,...&Wang, Pengfei.(2024).Vascular endothelial growth factor receptor 2 as a potential host target for the inhibition of enterovirus replication.JOURNAL OF VIROLOGY.

Zhao, Xiaoyu,et al."Vascular endothelial growth factor receptor 2 as a potential host target for the inhibition of enterovirus replication".JOURNAL OF VIROLOGY (2024).