RESUMEN
Analogues of the natural product cyclosporine A (CsA) were developed and assessed as antivirals against infection of hepatitis B virus (HBV) and its satellite hepatitis D virus (HDV). An analogue termed 27A exhibits potent inhibition of HBV/HDV infection by specifically blocking viral engagement to its cellular receptor NTCP, while it lacks immunosuppressive activity found in natural CsA. Intraperitoneal injection or oral intake of 27A protects HDV-susceptible mouse model from HDV infection. 27A serves as a promising lead for the development of novel anti-HDV/HBV agents.
Asunto(s)
Antivirales/uso terapéutico , Ciclosporina/uso terapéutico , Hepatitis B/tratamiento farmacológico , Hepatitis D/tratamiento farmacológico , Transportadores de Anión Orgánico Sodio-Dependiente/fisiología , Simportadores/fisiología , Administración Oral , Animales , Antivirales/administración & dosificación , Antivirales/farmacología , Ciclosporina/administración & dosificación , Ciclosporina/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Células Hep G2 , Hepatitis B/fisiopatología , Hepatitis D/fisiopatología , Humanos , Ratones , Ratones Endogámicos C57BLRESUMEN
Autophagy plays specific roles in host innate and adaptive immune responses to numerous intracellular pathogens, including Mycobacterium tuberculosis. The ESAT-6 and CFP-10 proteins are secreted by M. tuberculosis and play important roles in pathogenesis. We hypothesized that these two proteins may affect the autophagy function of host macrophages during infection with M. tuberculosis, thereby shaping the immune reaction toward the pathogen. Interestingly, we found that rapamycin-induced autophagy of macrophages infected with M. tuberculosis H37Rv enhanced localization of mycobacteria with autophagosomes and lysosomes. Ectopic expression of the ESAT-6/CFP-10 fusion in macrophages dramatically inhibited autophagosome formation, and M. tuberculosis survival inside infected macrophages was significantly affected as well. Further, M. tuberculosis viability was increased by the fusion protein. Expression levels of autophagy-related genes (ATG), especially atg8, also decreased (p<0.05). These results suggested that ESAT-6 and CFP-10 proteins play significant roles in autophagy formation in M. tuberculosis infection and that autophagosome formation is regulated through the expression of ATG.