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.
Journal reference: Proceedings of the National Academy of Sciences
Provided by Los Alamos National Laboratory
- Scientists Model Hepatitis C Virus May 25, 2007 | not rated yet | 0
- Early treatment is key to combating hepatitis C virus Aug 08, 2008 | not rated yet | 0
- Entry point for hepatitis C infection identified Jan 24, 2012 | not rated yet | 0
- Data suggest liver experts should take care when prescribing novel antiviral HCV drugs Apr 02, 2011 | not rated yet | 0
- Improved culture system for hepatitis C virus infection Jul 16, 2008 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Classical and Quantum Mechanics via Lie algebras
Apr 15, 2011 I'd like to open a discussion thread for version 2 of the draft of my book ''Classical and Quantum Mechanics via Lie algebras'', available online at http://lanl.arxiv.org/abs/0810.1019 , and for the...
- More from Physics Forums - Independent Research
More news stories
Bacteria resistant to the antibiotic colistin are also commonly resistant to antimicrobial substances made by the human body, according to a study in mBio, the online open-access journal of the American Society for Microb ...
Diseases, Conditions, Syndromes 3 hours ago | 5 / 5 (1) | 0
(AP)—Federal investigators probing the hantavirus outbreak blamed for three deaths at Yosemite National Park recommend that design changes to tent cabins and other lodging run by private concessionaires first be reviewed ...
Diseases, Conditions, Syndromes 9 hours ago | not rated yet | 0
A new diagnostic test for a worm infection that can lead to severe enlargement and deformities of the legs and genitals is far more sensitive than the currently used test, according to results of a field ...
Diseases, Conditions, Syndromes 9 hours ago | not rated yet | 0 |
A Saudi man who had contracted the coronavirus has died, raising the death toll in the kingdom from the SARS-like virus to 16, the health ministry announced on Monday on its Internet website.
Diseases, Conditions, Syndromes 11 hours ago | not rated yet | 0
A new "telerehabilitation" approach lets physical therapists assess patients with low back pain (LBP) over the Internet, with good accuracy compared with face-to-face examinations, reports a study in the May 15 issue of Sp ...
Diseases, Conditions, Syndromes 11 hours ago | not rated yet | 0
Early-life exposure to traffic-related air pollution was significantly associated with higher hyperactivity scores at age 7, according to new research from the University of Cincinnati (UC) and Cincinnati Children's Hospital ...
3 hours ago | not rated yet | 0 |
(Medical Xpress)—A research team, led by Jeremy Barr, a biology post-doctoral fellow, unveils a new immune system that protects humans and animals from infection.
8 hours ago | 4.6 / 5 (12) | 4 |
New research suggests that a compound abundant in the Mediterranean diet takes away cancer cells' "superpower" to escape death. By altering a very specific step in gene regulation, this compound essentially re-educates cancer ...
11 hours ago | 4.8 / 5 (11) | 2 |
Salamanders' immune systems are key to their remarkable ability to regrow limbs, and could also underpin their ability to regenerate spinal cords, brain tissue and even parts of their hearts, scientists have ...
12 hours ago | 4.8 / 5 (6) | 2 |
Researchers have pinpointed a catalytic trigger for the onset of Alzheimer's disease – when the fundamental structure of a protein molecule changes to cause a chain reaction that leads to the death of neurons ...
12 hours ago | 5 / 5 (3) | 0 |
Turns out, that old "practice makes perfect" adage may be overblown. New research led by Michigan State University's Zach Hambrick finds that a copious amount of practice is not enough to explain why people ...
9 hours ago | 3.3 / 5 (10) | 0 |