Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China.
National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Viruses. 2022 Jun 5;14(6):1228. doi: 10.3390/v14061228.
Flaviviruses, represented by Zika and dengue virus (ZIKV and DENV), are widely present around the world and cause various diseases with serious consequences. However, no antiviral drugs have been clinically approved for use against them. Azelnidipine (ALP) is a dihydropyridine calcium channel blocker and has been approved for use as an antihypertensive drug. In the present study, ALP was found to show potent anti-flavivirus activities in vitro and in vivo. ALP effectively prevented the cytopathic effect induced by ZIKV and DENV and inhibited the production of viral RNA and viral protein in a dose-dependent manner. Moreover, treatment with 0.3 mg/kg of ALP protected 88.89% of mice from lethal challenge. Furthermore, using the time-of-drug-addition assay, the enzymatic inhibition assay, the molecular docking, and the surface plasmon resonance assay, we revealed that ALP acted at the replication stage of the viral infection cycle by targeting the viral RNA-dependent RNA polymerase. These findings highlight the potential for the use of ALP as an antiviral agent to combat flavivirus infections.
黄病毒属（Flaviviruses），以寨卡病毒（Zika virus，ZIKV）和登革热病毒（Dengue virus，DENV）为代表，广泛存在于世界各地，可引起多种疾病，后果严重。然而，目前临床上尚未有针对它们的抗病毒药物被批准使用。阿折地平（Azelnidipine，ALP）是一种二氢吡啶类钙通道阻滞剂，已被批准用于治疗高血压。本研究发现，ALP 在体外和体内均具有很强的抗黄病毒活性。ALP 可有效预防 ZIKV 和 DENV 诱导的细胞病变效应，并呈剂量依赖性抑制病毒 RNA 和病毒蛋白的产生。此外，用 0.3mg/kg 的 ALP 治疗可使 88.89%的小鼠免受致死性攻击。进一步通过加药时间测定、酶抑制测定、分子对接和表面等离子体共振测定，揭示了 ALP 通过靶向病毒 RNA 依赖性 RNA 聚合酶，在病毒感染周期的复制阶段发挥作用。这些发现提示 ALP 有作为抗病毒药物用于治疗黄病毒感染的潜力。
