Host factors involved in viral replication are potentially attractive
antiviral targets that are complementary to specific inhibitors of viral
enzymes, since resistant mutations against the latter are likely to emerge during long-term treatment. It has been reported recently that
cyclosporine, which binds to a family of cellular
proteins,
cyclophilins, inhibits hepatitis C virus (HCV) replication in vitro. Here, the activities of various
cyclosporine derivatives were evaluated in the HCV replicon system. There was a strong correlation between the anti-HCV activity and
cyclophilin-binding affinity of these compounds. Of these,
NIM811 has been selected as a therapeutic candidate for HCV
infection, since it binds to
cyclophilins with higher affinity than
cyclosporine but is devoid of the significant immunosuppressive activity associated with
cyclosporine.
NIM811 induced a concentration-dependent reduction of HCV
RNA in the replicon cells with a 50% inhibitory concentration of 0.66 microM at 48 h. Furthermore, a greater than three-log(10)
viral RNA reduction was achieved after treating the cells with as little as 1 microM of
NIM811 for 9 days. In addition, the combination of
NIM811 with
alpha interferon significantly enhanced anti-HCV activities without causing any increase of cytotoxicity. Taken together, these promising in vitro data warrant clinical investigation of
NIM811, an inhibitor of novel mechanism, for the treatment of
hepatitis C.