RESUMEN
Nuclear export of the viral ribonucleoprotein (vRNP) is a critical step in the influenza A virus (IAV) life cycle and may be an effective target for the development of anti-IAV drugs. The host factor ras-related nuclear protein (RAN) is known to participate in the life cycle of several viruses, but its role in influenza virus replication remains unknown. In the present study, we aimed to determine the function of RAN in influenza virus replication using different cell lines and subtype strains. We found that RAN is essential for the nuclear export of vRNP, as it enhances the binding affinity of XPO1 toward the viral nuclear export protein NS2. Depletion of RAN constrained the vRNP complex in the nucleus and attenuated the replication of various subtypes of influenza virus. Using in silico compound screening, we identified that bepotastine could dissociate the RAN-XPO1-vRNP trimeric complex and exhibit potent antiviral activity against influenza virus both in vitro and in vivo. This study demonstrates the important role of RAN in IAV replication and suggests its potential use as an antiviral target.
Asunto(s)
Transporte Activo de Núcleo Celular , Antivirales , Proteína Exportina 1 , Virus de la Influenza A , Carioferinas , Replicación Viral , Proteína de Unión al GTP ran , Replicación Viral/efectos de los fármacos , Humanos , Proteína de Unión al GTP ran/metabolismo , Proteína de Unión al GTP ran/genética , Antivirales/farmacología , Animales , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/fisiología , Carioferinas/metabolismo , Carioferinas/antagonistas & inhibidores , Perros , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Células de Riñón Canino Madin Darby , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/genética , Ratones , Piperidinas/farmacología , Gripe Humana/virología , Células A549 , Nucleoproteínas/metabolismo , Nucleoproteínas/genética , Células HEK293 , Línea Celular , Núcleo Celular/metabolismo , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genéticaRESUMEN
In this study, polyvinylidene fluoride (PVDF) composite films were prepared by fused deposition modeling, and the effects of ionic liquid (IL) content on the printability, crystallization behavior, and electrical properties of melted PVDF were systematically investigated. The results show that the addition of IL increased the temperature sensitivity of melted PVDF and decreased its viscosity, while IL acted as a plasticizer to lower the melting point of PVDF and improve its FDM printability. The imidazole cations in IL had electrostatic interactions with the -CF2- groups in PVDF, which promoted the transformation of the nonpolar phase to the polar phase in PVDF; thus, the addition of IL was beneficial to the increase in the polar ß phase. The PVDF with 20 wt.% IL contained the highest proportion of ß phase content (32.59%). Moreover, the increase in polar ß-phase content also increased the polarization strength of PVDF and improved its ferroelectric properties. PVDF with 10 wt.% IL had the highest residual polarization strength (16.87 µC/m2).