Navigation Links
Computer modeling reveals how surprisingly potent hepatitis C drug works
Date:2/20/2013

LOS ALAMOS, N.M., Feb. 19, 2013A study by researchers from Los Alamos National Laboratory and a multinational team reveals how daclatasvir, a direct-acting antiviral agent in development for the treatment of hepatitis C virus (HCV), targets one of its proteins and causes the fastest viral decline ever seen with anti-HCV drugs within 12 hours of treatment.

Chronic infection with hepatitis C virus affects about 150 million people worldwide. It is the leading cause of cirrhosis, liver cancer and liver transplants and results in some 350,000 deaths worldwide every year.

The team's work reveals that daclatasvir has two primary modes of action against HCV and also provides a more accurate estimate of the HCV half-life. Until 2011, treatment options were limited and offered modest effectiveness; fewer than half of treated patients were fully cured of the virus. In the last decade, active research on understanding the mechanisms of HCV replication resulted in the discovery of direct acting antivirals targeting all stages of the viral replication process.

The new mathematical analysis of the rapid viral decline observed after one dose of daclatasvir reveals that the drug blocks two stages of the viral lifecycle and that the HCV half-life in serum is four times shorter than previously thought according to a study published in Proceedings of the National Academy of Sciences USA.

The NS5A protein within the hepatitis virus is a specific target for drug development. The first NS5A inhibitor, daclatasvir, developed by Bristol Myers Squibb, showed one of the most potent effects in combating HCV; one dose led to a thousand-fold decrease in viral levels within about 12 hours. Oddly, however NS5A has no known enzymatic functions making it difficult to understand its mode of action and design optimal drug combinations.

"Unraveling how this drug could cause such a rapid drop in the amount of virus in an infected person's blood could greatly enhance our ability to design optimal drug therapies and ultimately cure this disease," said Alan Perelson, senior author on the paper and a senior fellow at Los Alamos National Laboratory.

A mathematical method called "viral kinetic modeling" aims to characterize the main mechanisms that govern the virologic response to treatment. It is instrumental in understanding HCV pathogenesis and in guiding development of a variety of anti-HCV agents.

Until now, viral kinetic models did not take into account the intracellular events during viral replication and infected cells were considered as "black boxes" whose viral production was partially shut down by treatment.

The researchers demonstrated that understanding the effects of daclatasvir in vivo requires a novel modeling approach that incorporates drug effects on the HCV intracellular lifecycle. They used this new model to characterize the viral kinetics during daclatasvir therapy and they showed that this compound efficiently blocked two distinct processes, namely the synthesis of new viral genomes (like other antivirals) but also the release of the virus from infected cells.

As a consequence of this unique mode of action, the viral decline observed during treatment with daclatasvir allowed for more precise estimation of the HCV half-life in serum, about 45 minutes, instead of the previously estimated 2.7 hours. This implies that the daily viral production; and thus the risk of mutations conferring drug resistance, is four times larger than previously thought.


'/>"/>

Contact: Nancy Ambrosiano
nwa@lanl.gov
505-699-1149
DOE/Los Alamos National Laboratory
Source:Eurekalert

Related biology news :

1. New supercomputer to aid genomics research
2. New supercomputer coming to EMSL this summer, supplied by Atipa Technologies
3. Virginia Tech computer scientists develop new way to study molecular networks
4. Iowa State computer, electrical engineers working to help biologists cope with big data
5. How computers push on the molecules they simulate
6. Total donates high-speed computer cluster to UH
7. A better thought-controlled computer cursor
8. Computers taught to ID regulating gene sequences
9. Computer simulations for multiscale systems can be faster, better, more reliable
10. Computer viruses could take a lesson from showy peacocks
11. NPointer from Neurotechnology Uses Hand Gestures to Control and Navigate Computer Programs Without a Mouse or Touchpad
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/28/2016)... Sweden , April 28, 2016 First ... M (139.9), up 966% compared with the first quarter of 2015 ... profit totaled SEK 589.1 M (loss: 18.8) and the operating margin ... 7.12 (loss: 0.32) Cash flow from operations was SEK ... The 2016 revenue guidance is unchanged, SEK 7,000-8,500 M. ...
(Date:4/19/2016)... -- The new GEZE SecuLogic access control ... system solution for all door components. It can be ... interface with integration authorization management system, and thus fulfills ... dimensions of the access control and the optimum integration ... considerable freedom of design with regard to the doors. ...
(Date:4/14/2016)... BioCatch ™, the global ... the appointment of Eyal Goldwerger as CEO. ... Goldwerger,s leadership appointment comes at a time of significant ... of its platform at several of the world,s largest ... unique cognitive and physiological factors, is a winner of ...
Breaking Biology News(10 mins):
(Date:6/27/2016)... 27, 2016  Sequenom, Inc. (NASDAQ: SQNM ... lives through the development of innovative products and services, ... the United States denied its petition to ... of Sequenom,s U.S. Patent No. 6,258,540 (",540 Patent") are ... by the Supreme Court,s Mayo Collaborative Services v. Prometheus ...
(Date:6/27/2016)... , ... June 27, 2016 , ... ... bring innovative medical technologies, services and solutions to the healthcare market. The company's ... of various distribution, manufacturing, sales and marketing strategies that are necessary to help ...
(Date:6/27/2016)... , June 27, 2016   Ginkgo Bioworks ... to industrial engineering, was today awarded as one ... selection of the world,s most innovative companies. Ginkgo ... scale for the real world in the nutrition, ... engineers work directly with customers including Fortune 500 ...
(Date:6/24/2016)... ... June 24, 2016 , ... While the majority of commercial ... Cary 5000 and the 6000i models are higher end machines that use the more ... the spectrophotometer’s light beam from the bottom of the cuvette holder. , FireflySci ...
Breaking Biology Technology: