Twisting Hepatitis C Out Of Commission

Researchers have found how a new antihepatitis C agent works. When the hepatitis C virus (HCV) infects human cells, it co-opts the host’s protein-making machinery to make it mass-produce virus proteins. The single-stranded RNA virus takes over host protein translation because its 5' end has a structured, 90° bend that helps recruit an important host ribosomal subunit. Now, Darrell R. Davis, a biochemist at the University of Utah, and coworkers find that Isis-11, a benzimidazole-based antiviral agent, straightens out HCV’s 90° RNA bend. They propose that the inhibitor-induced structural change explains the scaffold’s antiviral activity (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas/0911896107). The team solved the NMR solution structure of the inhibitor bound to the portion of the virus’s RNA sequence that normally bends and found that two dimethylamino groups are important for the inhibitor-RNA interaction but that few additional contacts form in the coupling. The team hopes these and other structural insights will help chemists improve the molecule’s affinity for HCV and help lead to a better drug to fight the pathogen, infections from which currently cause 10,000 deaths per year in the U.S.