(Press-News.org) 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 liver transplantation in the U.S. Studies have shown that the current treatment of PEGylated interferon 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 therapeutic target," 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 proton channel within HCV infected cells, and that its function could be blocked by small molecule inhibitors, resulting in a blockade of infectious virus production.
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.
INFORMATION:
This study was conducted in collaboration with the laboratories of Professor Mark Harris, Professor Colin Fishwick and Dr. Richard Foster (University of Leeds), as well as Professor Steven Weinman (University of Kansas). Funding was through the UK Medical Research Council, Yorkshire Cancer Research and the University of Leeds Biomedical Health Research Centre.
Additional Media Contact:
Paula Gould
University of Leeds Communications & Press Office
+44 (0)113 343 8059
p.a.gould@leeds.ac.uk
This study is published in Hepatology. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.
Full Citation:
Article: "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. http://onlinelibrary.wiley.com/doi/10.1002/hep.24371/abstract.
About the Journal
Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350 .
About Wiley-Blackwell
Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.
END
This release is available in French.
Montreal, June 28, 2011 —Canadians aren't the only people concerned with weather, eh? A new study from McGill and Concordia universities observed pedestrians in nine cities around the world and found people are less likely to walk when temperatures dip below zero, when there's too much rain or too much snow. Published in the journal Environment and Behavior, the study was conducted over 170 days from late fall to early summer.
"A 5 degree Celsius increase in temperature was associated with a 14 per cent increase in pedestrians," ...
The Eatery on Beach Street has a new look on the inside and new menu items like Burger Diane and weekly specials like Friday's steak gone wild. The restaurant even has a new logo featuring a wine glass and new tagline.
The new logo and the new look are part of the restaurant's effort to attract a clientele that likes made-from-scratch American food with fresh ingredients and a creative twist.
"Chef Don likes to surprise patrons with a dish that mixes unexpected flavors or recreates a favorite recipe in a new form," said co-owner Cindy Gifford. She mentioned ...
New research confirms that a variant on the patatin-like phospholipase-3 (PNPLA3) gene increases risk of steatosis and fibrosis progression in patients with chronic hepatitis C virus (HCV). The PNPLA3 single nucleotide polymorphism (SNP) rs 738409 may represent an important genetic predictor and potential therapeutic target in chronic HCV liver damage. Study details are published in the July issue of Hepatology, a peer-reviewed journal of the American Association for the Study of Liver Diseases.
According to a report by the World Health Organization (WHO) roughly 170,000 ...
Bird species in rainforest fragments in Brazil that were isolated by deforestation disappeared then reappeared over a quarter-century, according to research results published today in the journal PLoS ONE.
Scientists thought many of the birds had gone extinct.
The research was funded by the National Science Foundation (NSF), and conducted in cooperation with Projeto Dinâmica Biológica de Fragmentos Florestais, Instituto Nacional de Pesquisas da Amazônia and the Smithsonian Tropical Research Institute in Manaus, Brazil.
Lead author Philip Stouffer, an ornithologist ...
From educators to leaders in industry, there is broad agreement that U.S. schools have a crucial challenge in improving teaching and learning in science, technology, engineering and math (STEM) among students from kindergarten through high school. A background in STEM is not only essential to many current and future careers; it is also a means for citizens to understand and participate in an increasingly complex world--from understanding the challenges of environmental sustainability to addressing the need for alternative sources of energy.
The NRC report, "Successful ...
New research by the University of Warwick and Humboldt university shows that the frequency of wars between states increased steadily from 1870 to 2001 by 2% a year on average. The research argues that conflict is being fed by economic growth and the proliferation of new borders.
We may think the world enjoyed periods of relative freedom from war between the Cold War and 9/1 but the new research by Professor Mark Harrison from at the University of Warwick's the Centre for Competitive Advantage in the Global Economy, and Professor Nikolaus Wolf from Humboldt University, ...
When Oxygen4Energy Athlete Kellie Wells got to Eugene, Oregon this past week, she had only one thing on her mind... winning a national championship. She knew that all of the nation's top competitors would also be there gunning for the title, but she was definitely up for the challenge.
So far this year, Kellie has been the most dominant figure in women's hurdles by tying an American Record (55m Hurdles), winning the Indoor National Title, running multiple World Lead times, winning the first Diamond League event, and never finishing worse than 2nd place in any race she ...
The global economic recession of 2008-09 has been followed by a decline in fertility rates in Europe and the United States, bringing to an end the first concerted rise in fertility rates in the developed world since the 1960s, according to research published today.
"In a new study, scientists from the Vienna Institute of Demography of the Austrian Academy of Sciences (VID) and the International Institute for Applied Systems Analysis (IIASA) identify that economic recessions tend to be followed by a decline in fertility rates - and also identify how specific groups of ...
Johns Hopkins University graduate students have invented a device to reduce the risk of infection, clotting and narrowing of the blood vessels in patients who need blood-cleansing dialysis because of kidney failure.
The device, designed to be implanted under the skin in a patient's leg, would give a technician easy access to the patient's bloodstream and could be easily opened and closed at the beginning and end of a dialysis procedure.
The prototype has not yet been used in human patients, but testing in animals has begun.
The students learned about the need for ...
Zinger Digital Signs today introduced eight new free-standing digital poster kiosk solutions for the retail and office/corporate markets. The digital signage poster kiosks are aimed at replacing printed posters used in retail and corporate environments. The new digital poster kiosks are certified for true 24/7 operations in commercial applications.
Digital posters offer many benefits to printed posters including savings from printing, shipping & handling. Digital posters can be updated instantly, giving retailers a tremendous benefit for those last minute sales or ...
