Asunto(s)
Urodinámica , Humanos , Urodinámica/fisiología , Vejiga Urinaria Neurogénica/terapia , Vejiga Urinaria Neurogénica/fisiopatología , Terapia por Estimulación Eléctrica/métodos , Micción/fisiología , Metaanálisis como Asunto , Revisiones Sistemáticas como Asunto , Síntomas del Sistema Urinario Inferior/terapia , Síntomas del Sistema Urinario Inferior/fisiopatologíaRESUMEN
Enterovirus A71 (EV-A71) is a human pathogen causing hand, foot and mouth disease (HFMD) which seriously threatened the safety and lives of infants and young children. However, there are no licensed direct antiviral agents to cure the HFMD. In this study, a series of quinoline formamide analogues as effective enterovirus inhibitors were developed, subsequent systematic structure-activity relationship (SAR) studies demonstrated that these quinoline formamide analogues exhibited good potency to treat EV-A71 infection. As described, the most efficient EV-A71 inhibitor 6i showed good anti-EV-A71 activity (EC50 = 1.238 µM) in RD cells. Furthermore, compound 6i could effectively prevent death of virus infected mice at dose of 6 mg/kg. When combined with emetine (0.1 mg/kg), this treatment could completely prevent the clinical symptoms and death of virus infected mice. Mechanism study indicated that compound 6i inhibited EV-A71 via targeting 2C helicase, thus impeding RNA remodeling and metabolism. Taken together, these data indicated that 6i is a promising EV-A71 inhibitor and worth extensive preclinical investigation as a lead compound.
Asunto(s)
Antivirales/farmacología , Dibucaína/farmacología , Enterovirus Humano A/efectos de los fármacos , Infecciones por Enterovirus/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , ARN Helicasas/antagonistas & inhibidores , Proteínas Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Dibucaína/síntesis química , Dibucaína/química , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Enterovirus Humano A/enzimología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Ratones , Ratones Endogámicos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , ARN Helicasas/metabolismo , Relación Estructura-Actividad , Proteínas Virales/metabolismoRESUMEN
Hexafluoroisopropanol (HFIP) was used as a phase-separation solvent to develop novel alcohol-salt aqueous two-phase systems (ATPSs) with various salts. Phase diagram and effective excluded volume (EEV) study proved that HFIP has much better phase-separation ability compared to traditional small molecule alcohols (ethanol, isopropanol and n-propanol). Then, the HFIP-NaCl ATPS was applied for the extraction and purification of chlorogenic acid (CGA) from ramie leaves. Under the optimum conditions (2 M NaCl solution with pH 3.0, the volume ratio of NaCl solution to HFIP at 6, vortex time 5 s and centrifugation time 7 min), the extraction efficiency of CGA in the salt-rich phase was 99.3%, meanwhile the HFIP-rich phase could extract a large amount of impurities. Furthermore, the CGA product with the purity of 91.0% was obtained from the salt-rich phase by semi-preparative liquid chromatography and salt removal, and its chemical structure was identified. Compared with other ATPSs, the HFIP-NaCl ATPS consumed much less organic solvent and salt, but acquired much higher extraction efficiency and obvious impurity-removal effect. Therefore, the HFIP-based alcohol-salt ATPSs are promising in the extraction and purification of CGA and other polar compounds as well.