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

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

  • J Virol. 2024 Oct 22;98(10):e0112924. doi: 10.1128/jvi.01129-24.
Xiaoyu Zhao # 1 2,  Rui Qiao # 2,  Meng Hao # 3,  Longfa Xu # 4,  Dong Wang 5,  Yinying Lu 1,  Jiayan Li 2,  Jing Wu 6,  Yi Li 7,  Tong Cheng 4,  Wenhong Zhang 6,  Jincun Zhao 5 8 9 10,  Pengfei Wang 2
Affiliations

Affiliations

  • 1 Shanghai Sci-Tech Inno Center for Infection & Immunity, National Medical Center for Infectious Diseases, Huashan Hospital, Institute of Infection and Health, Fudan University, Shanghai, China.
  • 2 Shanghai Pudong Hospital, Fudan University Pudong Medical Center, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China.
  • 3 Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
  • 4 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, China.
  • 5 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 6 Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
  • 7 Human Phenome Institute, Fudan University, Shanghai, China.
  • 8 Guangzhou Laboratory, Bio-Island, Guangzhou, China.
  • 9 Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 10 Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital; The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • # Contributed equally.
PMID: 39287389 DOI: 10.1128/jvi.01129-24
Abstract

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/KDR/Flk-1 knockdown and overexpression suppressed and facilitated EV-A71 replication, respectively, indicating that VEGFR2/KDR/Flk-1 is a novel host dependency factor for EV-A71 replication. Transcriptome analysis further proved that VEGFR2/KDR/Flk-1 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/KDR/Flk-1 may be a key host factor involved in EV-A71 replication, making it a potential target for the development of anti-enterovirus therapeutics.

Importance: 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/KDR/Flk-1 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.

Keywords

EV-A71; VEGFR family; VEGFR2; host factor; kinase inhibitors.

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