Scripps Research Scientists Identify Key Interaction In Hepatitis C Virus

[Guest guest]

Scripps Research Scientists Identify Key Interaction In

Hepatitis C Virus

30 Dec 2010

Scientists from the Florida campus of The Scripps Research Institute

have identified a molecular interaction between a structural

hepatitis C virus protein (HCV) and a protein critical to viral

replication. This new finding strongly suggests a novel method of

inhibiting the production of the virus and a potential new

therapeutic target for hepatitis C drug development.

The study was published in the January 2010 issue (Volume 92, Part

1) of the Journal of General Virology.

These new data underline the essential role of the viral protein

known as "core" as a primary organizer of the infectious HCV

particle assembly and support a new molecular understanding of the

formation of the viral particle itself.

"While our finding that the HCV core interacts with the

non-structural helicase protein was not totally unexpected, this had

not really been confirmed until this study," said Scripps Florida

Professor Donny Strosberg, who led the study. "But the most exciting

part is that small molecule inhibitors of dimerization [the joining

of two identical subunits] of core actually inhibit interaction

between core and helicase, thus possibly preventing production of an

infectious viral particle."

A Viral Plague

Hepatitis C virus infects between 130 and 170 million people

worldwide and is the cause of an epidemic of liver cirrhosis and

cancer. Because current HCV treatments are only partially effective,

a number of alternative molecular mechanisms are actively being

pursued as possible drug targets.

One of the critical problems of finding inhibitors for the hepatitis

C virus is that it mutates at such prodigious rates. An RNA virus

such as hepatitis C can mutate at a rate estimated as high as one

million times that of DNA viruses such as the herpes virus.

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.

The first author of the study, "Dimerization-Driven Interaction of

Hepatitis C Virus Core Protein with Ns3 Helicase," is Guillaume

Mousseau of Scripps Research. Additional authors include a

Kota, S. and Virginia Takahashi of Scripps Research, and Frick

of the University of Wisconsin, Milwaukee. For more information, see

http://vir.sgmjournals.org/cgi/content/abstract/92/1/101

The study was supported by the state of Florida, The Factor

Foundation, and the National Institutes of Health.

Article URL: http://www.medicalnewstoday.com/articles/212528.php

--

Bill Eastman

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