Computer Modeling Reveals How Surprisingly Potent Hepatitis C Drug Works

   Computer Modeling Reveals How Surprisingly Potent Hepatitis C Drug Works

PR Newswire

LOS ALAMOS, N.M., Feb. 19, 2013

LOS ALAMOS, N.M., Feb. 19, 2013 /PRNewswire-USNewswire/ -- A 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.

About the team

The study is by researchers Alan S. Perelson from Los Alamos National
Laboratory, Susan L. Uprichard and Natasha Sansone from University of Illinois
at Chicago; Harel Dahari, Thomas Layden and Scott J. Cotler from Loyola
University, Chicago; Richard Nettles from Bristol-Myers Squibb and Jeremie
Guedj from Institut National de la Santé et de la Recherche Médicale, France.

The research was funded by National Institutes of Health, the National Science
Foundation and the University of Illinois Walter Payton Liver Center Guild.

Link to paper online:  "Modeling shows that the NS5A inhibitor daclatasvir has
two modes of action and yields a shorter estimate of the hepatitis C virus
half-life," at
http://www.pnas.org/content/early/2013/02/13/1203110110.abstract

About Los Alamos National Laboratory (www.lanl.gov)

Los Alamos National Laboratory, a multidisciplinary research institution
engaged in strategic science on behalf of national security, is operated by
Los Alamos National Security, LLC, a team composed of Bechtel National, the
University of California, The Babcock & Wilcox Company and URS Corporation for
the Department of Energy's National Nuclear Security Administration.

Los Alamos enhances national security by ensuring the safety and reliability
of the U.S. nuclear stockpile, developing technologies to reduce threats from
weapons of mass destruction, and solving problems related to energy,
environment, infrastructure, health and global security concerns.

SOURCE Los Alamos National Laboratory

Website: http://www.lanl.gov
Contact: Nancy Ambrosiano, +1-505-667-0471, nwa@lanl.gov
 
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