PDF(Pubmed)
Abstract：
Endocytosis, or internalization through endosomes, is a major cell entry mechanism used by respiratory viruses. Phosphoinositide 5-kinase (PIKfyve) is a critical enzyme for the synthesis of phosphatidylinositol (3, 5)biphosphate (PtdIns (3, 5)P2) and has been implicated in virus trafficking via the endocytic pathway. In fact, antiviral effects of PIKfyve inhibitors against SARS-CoV-2 and Ebola have been reported, but there is little evidence regarding other respiratory viruses. In this study, we demonstrated the antiviral effects of PIKfyve inhibitors on influenza virus and respiratory syncytial virus in vitro and in vivo. PIKfyve inhibitors Apilimod mesylate (AM) and YM201636 concentration-dependently inhibited several influenza strains in an MDCK cell-cytopathic assay. AM also reduced the viral load and cytokine release, while improving the cell integrity of human nasal air-liquid interface cultured epithelium infected with influenza PR8. In PR8-infected mice, AM (2 mg/mL), when intranasally treated, exhibited a significant reduction of viral load and inflammation and inhibited weight loss caused by influenza infection, with effects being similar to oral oseltamivir (10 mg/kg). In addition, AM demonstrated antiviral effects in RSV A2-infected human nasal epithelium in vitro and mouse in vivo, with an equivalent effect to that of ribavirin. AM also showed antiviral effects against human rhinovirus and seasonal coronavirus in vitro. Thus, PIKfyve is found to be involved in influenza and RSV infection, and PIKfyve inhibitor is a promising molecule for a pan-viral approach against respiratory viruses.
摘要：
胞吞作用,或通过内体内化，是呼吸道病毒使用的主要细胞进入机制。磷酸肌醇5-激酶（PIKfyve）是合成磷脂酰肌醇（3，5）磷酸二氢盐（PtdIns（3，5）P2）的关键酶，并已通过内吞途径参与病毒运输。事实上,PIKfyve抑制剂对SARS-CoV-2和埃博拉病毒的抗病毒作用已有报道，但是关于其他呼吸道病毒的证据很少。在这项研究中,我们在体外和体内证明了PIKfyve抑制剂对流感病毒和呼吸道合胞病毒的抗病毒作用.PIKfyve抑制剂阿吡莫德甲磺酸酯（AM）和YM201636在MDCK细胞病变测定中浓度依赖性地抑制了几种流感毒株。AM也减少了病毒载量和细胞因子的释放，同时提高人鼻腔气-液界面培养的感染流感PR8的上皮细胞的完整性。在PR8感染的小鼠中，AM（2mg/mL），当鼻内治疗时，表现出病毒载量和炎症的显着减少，并抑制了由流感感染引起的体重减轻，效果类似于口服奥司他韦（10mg/kg）。此外,AM在体外和体内小鼠中在RSVA2感染的人鼻上皮中表现出抗病毒作用，效果与利巴韦林相当。AM还在体外显示出对人类鼻病毒和季节性冠状病毒的抗病毒作用。因此，PIKfyve被发现与流感和RSV感染有关，和PIKfyve抑制剂是一种有前途的分子，用于抗呼吸道病毒的泛病毒方法。
