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| |  HCV Entry Pathway as a Target for Drug Development: Presented at HEP-DART By Barbara J. Rutledge, PhD LAHAINA, HAWAII -- December 18, 2007 -- Numerous steps in the complex HCV entry process appear amenable to therapeutic intervention, according to a researcher speaking here at HEP-DART 2007 Frontiers in Drug Development for Viral Hepatitis symposium. "The HCV entry process requires interactions between the virion and many cellular factors, as well as cellular processes such as endocytosis and endosomal functions," said Matthew J. Evans, PhD, Postdoctoral Fellow in the laboratory of Charles Rice, PhD, Maurice R. and Corinne P. Greenberg Professor, Rockefeller University, Scientific and Executive Director, Center for the Study of Hepatitis C, New York, New York, United States. Cellular processes, such as clathrin-mediated endocytosis or endosome formation or function, are probably not very clean targets, and agents designed to target those processes would be likely to have severe adverse effects, Dr. Evans said in his presentation on December 12. Another approach, modelled on the successes of the HIV coreceptor inhibitor and the HIV fusion inhibitor, would be to inhibit the interaction between cellular and viral entry factors using small peptides or antibodies. Agents that bind host factors may interfere with normal cellular functions, resulting in an unacceptable adverse effect profile. Agents that bind viral components in the entry process, such as the HCV envelope proteins, might be less likely to have severe adverse effects, but more likely to generate drug resistance. Glycosylation of the HCV envelope proteins could be targeted by glucosidase inhibitors and carbohydrate binding agents. One of the few HCV entry inhibitors already in clinical development is celgosivir (MX-3253), an orally administered alpha-glucosidase I inhibitor under development by Migenix. Celgosivir appears to be well tolerated and is currently in phase 2 clinical trials for treatment of chronic hepatitis C, genotype 1. Whether therapeutic inhibition of HCV entry could be curative would depend on factors such as the proportion of infected cells, how quickly the liver could regenerate, and whether naive cells could out-compete virus-infected cells. If only a low proportion of cells were infected, then protecting naive cells by entry inhibition would be predicted to have an impact, explained Dr. Evans. If a high proportion of cells were already infected, protection would likely be less important as a therapeutic goal. An entry inhibitor might be most effective in combination with RNA replication inhibitors. Cells cured of HCV by the replication inhibitor could be protected from reinfection by the entry inhibitor, and stopping viral spread could help prevent amplification of resistant mutants. "Entry inhibitors may be particularly helpful after liver transplantation, where universal reinfection of the graft often results in rapid fibrosis progression and subsequent graft failure," said Dr. Evans. "Even therapies transiently inhibiting HCV cell entry could prevent graft reinfection and thus greatly improve the effectiveness of liver transplantation." Dr. Evans reports no conflicts of interest.
[Presentation title: HCV Entry Pathways and Implications for the Development of Entry Inhibitors. Abstract 53]
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