The Core of the Matter
Core, the most conserved protein among all HCV genotypes, plays several essential roles in the viral cycle in the host cell; studies have suggested that these core-core or core-other protein interactions can modulate various functions including signaling, apoptosis or programmed cell death, lipid metabolism, and gene transcription.
The core protein is particularly important in the assembly of the hepatitis C nucleocapsid, an essential step in the formation of infectious viral particles; the nucleocapsid is the viral genome protected by a protein coat – the capsid. This core protein plays an essential role in the HCV cycle during assembly and release of the infectious virus, as well as disassembly of viral particles upon entering host cells.
Looking closely at the core interaction with itself, Strosberg developed several novel quantitative assays or tests for monitoring these protein-protein interactions with the specific goal of identifying inhibitors of the core dimerization, which would block virus production.
"People have been dreaming about inhibiting protein-protein interactions, as a new El Dorado for finding novel drug targets," says Strosberg, "but few conclusive studies have emerged, except in the virus-host area."
Inhibition of HCV Production
The new research, however, led to the discovery of two peptides that inhibited HCV production by 68 percent and 63 percent, respectively; a third related peptide showed 50 percent inhibition. When added to HCV-infected cells, each of the three peptides blocked release but not replication of infectious virus; viral RNA levels were reduced by seven fold. Strosberg notes that the efficacy of small molecules like these can often be improved over initial levels.
"After we'd finished our work, we learned that Frank Chisari – one of the leading experts on HCV who work
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