Hindered nucleoside analogs as inhibitors of HCV RNA-dependent RNA-polymerase: evolving vistas.

The inability of current therapies to achieve a high sustained viral response with all HCV infections highlights the necessaty of developing more potent and braoad-spectrum inhibitors of all the HCV genotypes. The most promising antiviral target viral proteins or processes that are not endogenous to host cells. Close structural homologs of the HCV RNA-dependent RNA polymerase (RdRp) do not exist within the uninfected host cell; thus, this protein represents an excellent target for antiviral therapy. Under these perspectives, different series of new nucleoside analogs have been designed and obtained by means of simple synthetic routes. Among the plethora of synthesized compounds, a number of different anologs have shown interesting activity data, comparable to ribavirin, the unique nucleoside analogue currently approved for HCV therapy, when tested for biological activity on cell cultures infected by bovine viral diarrhea virus (BVDV), the pathogen most widely employed as HCV surrogate. Based on these encouraging results, an explorative molecular modelling study has been undertaken to investigate the interactions between the most probable molecular target (RdRp) and the most promising drug candidates, in order to derive a structure-activity relationship, aimed at designing further generations of derivatives with enhanced potency.