In vitro Anti-Hantavirus Activity of Protein Kinase Inhibitor 8G1 Targeting AKT/mTOR/eIF4E Signaling Pathway.
In vitro Anti-Hantavirus Activity of Protein Kinase Inhibitor 8G1 Targeting AKT/mTOR/eIF4E Signaling Pathway.
复制标题
DOI：
10.3389/fmicb.2022.880258
复制
发表时间：
2022
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
作者：
汉滩病毒（HTNV）是引起肾综合征出血热（HFRS）的主要病原，在世界范围内引起严重的发病率和死亡率。然而，目前没有FDA批准的针对HFRS的治疗剂或疫苗。为了寻找新的抗HTNV药物，分析了901种小分子激酶抑制剂对HTNV的抑制活性。在这些化合物中，化合物8 G1以相对高的抑制率和较低的毒性抑制HTNV。HTNV的病毒滴度和核衣壳蛋白在化合物8 G1处理后以剂量依赖性方式在1至20 μM的浓度范围内降低。此外，在HTNV感染的早期阶段施用化合物8 G1可以抑制HTNV的复制。分子对接结果表明，化合物8 G1与丝氨酸/苏氨酸蛋白激酶B（Akt）的关键氨基酸残基形成相互作用，这是观察到的亲和力的原因。然后，哺乳动物雷帕霉素靶蛋白（mTOR）和真核生物翻译起始因子4 E（eIF 4 E）信号通路被抑制。我们的研究结果可能有助于设计新的靶点用于治疗HTNV感染，并了解蛋白激酶抑制剂的抗HTNV机制。
Hantaan virus (HTNV) is the main cause of hemorrhagic fever with renal syndrome (HFRS) around the world, which results in profound morbidity and mortality. However, there are currently no FDA-approved therapeutics or vaccines against HFRS. To find new anti-HTNV drugs, the inhibitory activity of 901 small molecule kinase inhibitors against HTNV is analyzed. Among these compounds, compound 8G1 inhibits HTNV with a relatively high inhibition rate and lower toxicity. The viral titer and nucleocapsid protein of HTNV are reduced after compound 8G1 treatment in a dose-dependent manner at concentrations ranging from 1 to 20 μM. In addition, the administration of compound 8G1 at the early stage of HTNV infection can inhibit the replication of HTNV. The molecular docking result reveals that compound 8G1 forms interactions with the key amino acid residues of serine/threonine-protein kinase B (Akt), which is responsible for the observed affinity. Then, the mammalian target of rapamycin (mTOR) and eukaryotic translation initiation factor 4E (eIF4E) signaling pathways are inhibited. Our results may help to design novel targets for therapeutic intervention against HTNV infection and to understand the anti-HTNV mechanism of protein kinase inhibitors.