RESUMEN
Antiviral drug resistance in influenza infections has been a major threat to public health. To develop a broad-spectrum inhibitor of influenza to combat the problem of drug resistance, we previously identified the highly conserved E339...R416 salt bridge of the nucleoprotein trimer as a target and compound 1 as an inhibitor disrupting the salt bridge with an EC50 = 2.7 µM against influenza A (A/WSN/1933). We have further modified this compound via a structure-based approach and performed antiviral activity screening to identify compounds 29 and 30 with EC50 values of 110 and 120 nM, respectively, and without measurable host cell cytotoxicity. Compared to the clinically used neuraminidase inhibitors, these two compounds showed better activity profiles against drug-resistant influenza A strains, as well as influenza B, and improved survival of influenza-infected mice.
Asunto(s)
Compuestos de Anilina/farmacología , Antivirales/farmacología , Virus de la Influenza A/química , Multimerización de Proteína/efectos de los fármacos , Proteínas de Unión al ARN/metabolismo , Tiazoles/farmacología , Proteínas del Núcleo Viral/metabolismo , Compuestos de Anilina/síntesis química , Compuestos de Anilina/metabolismo , Animales , Antivirales/síntesis química , Antivirales/metabolismo , Sitios de Unión/efectos de los fármacos , Femenino , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteínas de la Nucleocápside , Unión Proteica , Electricidad Estática , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/metabolismoRESUMEN
Glycosylation of lipids and proteins is not encoded by genes directly and depends on many factors including the origin of cell-lines, differential expression of carbohydrate enzymes and availability of substrates, as well as environmental conditions. Individual cells from different tissues produce each glycoprotein as heterogeneous mixtures of glycoforms with distinct biological activities in response to different conditions and disease states. As the result, the study of glycosylation could not rely purely on biochemical methods; instead it requires a multidisciplinary approach utilizing a variety of methods including genetic manipulation and glycosylation pathway engineering, structural and functional proteomic analysis, chemical and enzymatic synthesis, development of glycosylation probes and glycan microarrays. This review highlights recent progress and demonstrates how the availability of structure-defined oligosaccharides enables development of new and improved therapies, such as therapeutic homogeneous antibodies and carbohydrate-based vaccines against cancer.