P7 protein resistance mutations identified; represent drug targets for hepatitis C virus

British researchers have identified specific resistance mutations for two classes of p7 inhibitor, which may explain their lack of effectiveness in clinical trials combined with current standard of care. Study results support the role of p7 inhibitor combinations as potential components of future HCV-specific therapies and are available in the July issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.

More than 3% of the world population is infected with HCV, which causes severe liver disease. HCV is the leading cause of liver-related mortality and most common cause for in the U.S. Studies have shown that the current treatment of alpha (IFN) and ribavirin (Rib) does not adequately achieve a sustained virological response in many HCV patients. This, coupled with the high cost and poor patient compliance, continues to drive demand for new virus-specific therapies.

"The HCV p7 ion channel plays a critical role in infectious virus production, representing an important new ," said lead researcher Dr. Stephen Griffin with the Institute of Molecular Medicine at the University of Leeds in the UK. Previously, Dr. Griffin and colleagues determined that p7 acts as a within HCV infected cells, and that its function could be blocked by small , resulting in a blockade of infectious .

In the present study, the team set out to expand on their prior work by predicting inhibitor binding sites using molecular modeling, which were then validated by the identification of resistance mutations. This allowed the researchers to define the mode of action for two prototype p7 inhibitor classes—adamantanes (amantadine and rimantadine) and alkylated imino-sugars (IS). This confirmed not only specific, but distinct effects for these inhibitors on the p7 protein. As these drugs are known to be safe in humans, they could rapidly be combined with new direct-acting HCV drugs, while paving the way for the development of novel, more potent compounds.

Dr. Griffin explains, "Our study confirms that single amino acid changes can mediate resistance to p7 inhibitor drugs." The study describes that low fitness cost for the observed mutations suggest that a minimal genetic barrier to their selection exists, which explains the perceived lack of p7 inhibitor efficacy in clinical trials combined with IFN/Rib. "Further investigation into the molecular basis of p7 drug resistance will aid in the design of novel, more effective therapies to combat HCV," concluded Dr. Griffin.

More information: "Resistance Mutations Define Specific Antiviral Effects for Inhibitors of the Hepatitis C Virus (HCV) P7 Ion Channel." Toshana L. Foster, Mark Verow, Ann L. Wozniak, Matthew J. Bentham, Joseph Thompson, Elizabeth Atkins, Steven A. Weinman, Colin Fishwick, Richard Foster, Mark Harris and Stephen Griffin. Hepatology; Published Online: June 24, 2011 (DOI: 10.1002/hep.24371); Print Issue Date: July 2011.

add to favorites email to friend print save as pdf

Related Stories

Recommended for you

At one month, US Ebola monitors finding no cases

1 hour ago

The U.S. program that requires weeks of monitoring for travelers from African countries with Ebola reaches the one-month mark Thursday. And so far, no cases of the disease have turned up.

EU calls for 5,000 doctors to fight Ebola

1 hour ago

The European Commission called for 5,000 doctors to be sent from EU states to combat west Africa's Ebola epidemic, a European source with knowledge of the matter said on Wednesday.

Guinea, hit by Ebola, reports only one cholera case

1 hour ago

The health workers rode on canoes and rickety boats to deliver cholera vaccines to remote islands in Guinea. Months later, the country has recorded only one confirmed cholera case this year, down from thousands.

Sierra Leone official: Ebola worst could be over

1 hour ago

The Ebola outbreak in Sierra Leone, which has been surging in recent days, may have reached its peak and be on the verge of slowing down, Sierra Leone's information minister said Wednesday.

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.