RESUMEN
Direct-acting antiviral inhibitors have revolutionized the treatment of hepatitis C virus (HCV) infected patients. Herein is described the discovery of velpatasvir (VEL, GS-5816), a potent pan-genotypic HCV NS5A inhibitor that is a component of the only approved pan-genotypic single-tablet regimens (STRs) for the cure of HCV infection. VEL combined with sofosbuvir (SOF) is Epclusa®, an STR with 98% cure-rates for genotype 1-6 HCV infected patients. Addition of the pan-genotypic HCV NS3/4A protease inhibitor voxilaprevir to SOF/VEL is the STR Vosevi®, which affords 97% cure-rates for genotype 1-6 HCV patients who have previously failed another treatment regimen.
Asunto(s)
Antivirales/farmacología , Carbamatos/farmacología , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Carbamatos/síntesis química , Carbamatos/química , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Genotipo , Hepacivirus/genética , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Compuestos Macrocíclicos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Sofosbuvir/química , Relación Estructura-Actividad , Sulfonamidas/química , Comprimidos/química , Comprimidos/farmacología , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
The rhs genes are a family of enigmatic composite genes, widespread among Gram-negative bacteria. In this study, we characterized rhsT, a Pseudomonas aeruginosa rhs gene that encodes a toxic protein. Expression of rhsT was induced upon contact with phagocytic cells. The RhsT protein was exposed on the bacterial surface and translocated into phagocytic cells; these cells subsequently underwent inflammasome-mediated death. Moreover, RhsT enhanced host secretion of the potent proinflammatory cytokines IL-1ß and IL-18 in an inflammasome-dependent manner. In a mouse model of acute pneumonia, infection with a P. aeruginosa strain lacking rhsT was associated with less IL-18 production, fewer recruited leukocytes, reduced pulmonary bacterial load, and enhanced animal survival. Thus, rhsT encodes a virulence determinant that activates the inflammasome.
Asunto(s)
Toxinas Bacterianas/genética , Inflamasomas/metabolismo , Neumonía/inmunología , Pseudomonas aeruginosa/genética , Factores de Virulencia/genética , Animales , Línea Celular , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Indirecta , Immunoblotting , Péptidos y Proteínas de Señalización Intercelular , Interleucina-1beta/metabolismo , Espectrometría de Masas , Ratones , Ratones Endogámicos BALB C , Fagocitos/metabolismo , Neumonía/microbiología , Reacción en Cadena en Tiempo Real de la Polimerasa , Espectrometría de Masas en Tándem , TransfecciónRESUMEN
Mutation of the gene drop-dead (drd) causes adult Drosophila to die within 2 weeks of eclosion and is associated with reduced rates of defecation and increased volumes of crop contents. In the current study, we demonstrate that flies carrying the strong allele drd(lwf) display a reduction in the transfer of ingested food from the crop to the midgut, as measured both as a change in the steady-state distribution of food within the gut and also in the rates of crop emptying and midgut filling following a single meal. Mutant flies have abnormal triglyceride (TG) and glycogen stores over the first 4 days post-eclosion, consistent with their inability to move food into the midgut for digestion and nutrient absorption. However, the lifespan of mutants was dependent upon food presence and quality, suggesting that at least some individual flies were able to digest some food. Finally, spontaneous motility of the crop was abnormal in drd(lwf) flies, with the crops of mutant flies contracting significantly more rapidly than those of heterozygous controls. We therefore hypothesize that mutation of drd causes a structural or regulatory defect that inhibits the entry of food into the midgut.