Computer modeling reveals how surprisingly potent hepatitis C drug works

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.

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.

Related Stories

Scientists Model Hepatitis C Virus

May 25, 2007

One of the most common life-threatening viral infections in the United States today is hepatitis C virus (HCV). The standard treatment is successful in only about 50 percent of treated HCV chronic patients, with no effective ...

Early treatment is key to combating hepatitis C virus

Aug 08, 2008

Canadian researchers have shown that patients who receive early treatment for Hepatitis C virus (HCV) within the first months following an infection, develop a rapid poly-functional immune response against HCV similar to ...

Entry point for hepatitis C infection identified

Jan 24, 2012

A molecule embedded in the membrane of human liver cells that aids in cholesterol absorption also allows the entry of hepatitis C virus, the first step in hepatitis C infection, according to research at the University of ...

Improved culture system for hepatitis C virus infection

Jul 16, 2008

A University of California, San Diego School of Medicine researcher has developed the first tissue culture of normal, human liver cells that can model infection with the Hepatitis C virus (HCV) and provide a realistic environment ...

Recommended for you

Dengue fever strikes models in Japan

29 minutes ago

A worsening outbreak of dengue fever in Japan has claimed its first celebrities—two young models sent on assignment to the Tokyo park believed to be its source.

Japanese researchers develop 30-minute Ebola test

30 minutes ago

Japanese researchers said Tuesday they had developed a new method to detect the presence of the Ebola virus in 30 minutes, with technology that could allow doctors to quickly diagnose infection.

Senegal monitors contacts of 1st Ebola patient

12 hours ago

Senegalese authorities on Monday were monitoring everyone who was in contact with a student infected with Ebola who crossed into the country, and who has lost three family members to the disease.

Cerebral palsy may be hereditary

18 hours ago

Cerebral palsy is a neurological developmental disorder which follows an injury to the immature brain before, during or after birth. The resulting condition affects the child's ability to move and in some ...

19 new dengue cases in Japan, linked to Tokyo park

Sep 01, 2014

Japan is urging local authorities to be on the lookout for further outbreaks of dengue fever, after confirming another 19 cases that were contracted at a popular local park in downtown Tokyo.

User comments