Brivanib alaninate inhibited dengue virus proliferation through VEGFR2/AMPK pathway
| Autor: | Liren Li, Xingang Yao, Wenyu Wu, Shuwen Liu, Jiawen Zhang, Xiaoguang Chen, Yuanda Wan, Yihong Wan |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class viruses AMP-Activated Protein Kinases Dengue virus Pharmacology Virus Replication medicine.disease_cause Antiviral Agents Dengue Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Oral administration medicine Animals Humans Phosphorylation Cells Cultured Protein Tyrosine Phosphatase Non-Receptor Type 1 Alanine Triazines business.industry Endothelial Cells virus diseases AMPK Dengue Virus biochemical phenomena metabolism and nutrition Vascular Endothelial Growth Factor Receptor-2 Disease Models Animal 030104 developmental biology Brivanib alaninate Viral replication chemistry 030220 oncology & carcinogenesis Host-Pathogen Interactions Viral disease business Signal Transduction |
| Zdroj: | Pharmacological Research. 170:105721 |
| ISSN: | 1043-6618 |
| DOI: | 10.1016/j.phrs.2021.105721 |
| Popis: | Dengue virus (DENV) is the most prevalent arthropod-borne viral disease of humans and has a major impact on global public health. There is no clinically approved drugs for DENV infection. Since intracellular VEGFR2 is increased in DENV infected patients, we thus hypothesized that VEGFR2 participated DENV proliferation and its inhibitors could be served as antivirals against DENV. Actually our results showed that VEGFR2 was induced by DENV infection. Also the agonist of VEGFR2, VEGF-A, promoted DENV proliferation. Therefore, we screened the inhibitors of VEGFR2 and found that brivanib alaninate (brivanib) showed the best anti-DENV ability with the lowest cellular cytotoxicity. Mechanically, our results indicated VEGFR2 directly interacted with PTP1B to dephosphorylate AMPK to provide lipid environment for viral replication. However, this effect could be inhibited by brivanib, which significantly reversed the reduction of AMPK phosphorylation caused by DENV infection, thus improving the cellular lipid environment. Moreover, the antiviral effect of brivanib could be reversed by AMPK inhibitor, Compound C. In addition, oral administration of brivianib (20–50 mg/kg/day) clearly improved the survival rate of DENV2 infection, and this effect was abolished in accompanied with Compound C (10mg/kg/day). Collectively, our study disclosed the mechanism of VEGFR2 in DENV2 and evaluated the antiviral ability of brivanib, which deserved more attention for clinical usage in DENV infection. |
| Databáze: | OpenAIRE |
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