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Molecular interaction between structural HCV protein and protein critical to viral replication identified

March 03, 2017

With this in mind, Strosberg has been examining the core protein, the most conserved protein among all HCV genotypes. Core plays several essential roles in the viral cycle in the host cell. It is particularly important in the assembly of the hepatitis C nucleocapsid or capsid, an essential step in the formation of infectious viral particles; the nucleocapsid is the virus genome protected by a protein coat. By interacting with various structural and non-structural viral proteins, core 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. Core also interacts with a number of cellular proteins, possibly contributing to the disarmament of several host defense mechanisms and to the activation of oncogenic pathways.

Last year, Strosberg developed a novel quantitative test for monitoring these protein-protein interactions with the specific goal of identifying inhibitors of the core dimerization, which would block virus production. Strosberg and his colleagues uncovered peptides derived from the core protein of hepatitis C that inhibit not only dimerization of the core protein, but also production of the actual virus.

That earlier study led to the discovery of non-peptidic small organic molecules that strongly inhibited HCV production, one of which, SL201, was used in the new study.

In the new study, Strosberg and his colleagues focused on non-structural proteins that provide functions relating to HCV production, in particular NS3 helicase. The scientists' findings support a growing body of evidence that this protein participates in the assembly and production of infectious viral particles. The interaction of the core protein with this non-structural protein also confirms core as a key organizer of virus assembly and suggests it acts to facilitate the packaging and integration of the newly synthesized viral RNA.

Source: Scripps Research Institute