A Perspective on Host Cell Targets and Inhibitors
from: Hepatitis C: Antiviral Drug Discovery and Development (Edited by: Seng-Lai Tan and Yupeng He). Caister Academic Press, U.K. (2011)
HCV drug discovery efforts have been mainly focusing on two viral targets, NS3 protease and NS5B polymerase, which are essential for viral replication. However, due to the high heterogeneity and high replication and mutation rates of the virus, resistance emerges quickly in patients treated with specific inhibitors of these viral enzymes. A complementary strategy is to target cellular proteins that are required for viral replication, which may have the advantage of higher genetic barrier to resistance and broader genotype coverage. Through siRNA screen and chemogenetic approach, a number of potential host targets have been identified at essentially every step of viral life cycle, including viral entry, genome replication, virion assembly and release. Some are engaged in viral replication through direct interaction with HCV proteins, such as cyclophilins. Others modulate viral life cycle via various cellular pathways, such as lipid metabolism and membrane trafficking. There exist both opportunities and challenges in developing host targeting antivirals. Currently the most advanced compounds are cyclophilin inhibitors in Ph II. The combination of host and viral targeting inhibitors presents a highly attractive strategy to suppress the emergence of resistance and maximize antiviral efficacy read more ...