RESUMEN
Recent evidence suggests that fibrotic liver injury in patients with chronic hepatitis C correlates with cellular senescence in damaged liver tissue. However, it is still unclear how senescence can affect replication of the hepatitis C virus (HCV). In this work, we report that an inhibitor of cyclin-dependent kinases 4/6, palbociclib, not only induced in hepatoma cells a pre-senescent cellular phenotype, including G1 arrest in the cell cycle, but also accelerated viral replicon multiplication. Importantly, suppression of HCV replication by direct acting antivirals (DAAs) was barely affected by pre-senescence induction, and vice versa, the antiviral activities of host-targeting agents (HTAs), such as inhibitors of human histone deacetylases (HDACi), produced a wide range of reactions-from a dramatic reduction to a noticeable increase. It is very likely that under conditions of the G1 arrest in the cell cycle, HDACi exhibit their actual antiviral potency, since their inherent anticancer activity that complicates the interpretation of test results is minimized.
Asunto(s)
Senescencia Celular/fisiología , Hepacivirus/metabolismo , Replicación Viral/fisiología , Antivirales/farmacología , Carcinoma Hepatocelular/metabolismo , Línea Celular , Genotipo , Hepacivirus/genética , Hepacivirus/patogenicidad , Hepatitis C/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Hígado/patología , Fenotipo , Piperazinas/farmacología , Piridinas/farmacología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
A set of ortho-, meta- and para-substituted cinnamic hydroxamic acids (CHAs) was synthesized. In each series of structural isomers, a phenyl substituent was linked to an aromatic ring of the parent cinnamic acid via a linker of one to four atoms in length. Using a cell test system with the full-length replicon of hepatitis C virus (HCV), we established a relationship between the suppression of HCV replicon propagation and the inhibition of class I/IIb histone deacetylases (HDACs). Anti-HCV activity correlated with the inhibition of HDAC8 in the case of ortho-CHAs, while in the case of meta-CHAs it correlated with the inhibition of HDAC1/2/3 and HDAC6. The antiviral activity of para-CHAs was many times stronger than that of meta-CHAs with about the same efficiency of HDAC1/2/3/6 inhibition, which indicated the existence of an additional cell target that does not belong to the studied group of HDACs.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Cinamatos/química , Cinamatos/farmacología , Hepacivirus/efectos de los fármacos , Hepacivirus/fisiología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Humanos , Isomerismo , Replicación Viral/efectos de los fármacosRESUMEN
N'-Propylhydrazide analogs of hydroxamic inhibitors of histone deacetylases (HDACs), including tubastatin A, vorinostat and belinostat, were synthesized. All prepared compounds inhibited HDAC1/2/3, but not HDAC6, except for one hydrazide analog of HDAC4/5/7 inhibitor that was completely inactive. A novel 4-substituted derivative of N'-propylbenzohydrazide with extremely high anti-HCV activity was discovered.