Old anti-itching drug shows promise against Hepatitis CSeptember 1st, 2008 - 4:40 pm ICT by IANS
Washington, Sep 1 (IANS) The fight against hepatitis C, which infects more than 150 million people, has been unable to make headway for years.Traditional antiviral treatments cause nasty side effects, often falling short of a cure. However, Stanford University researchers have discovered a vulnerable step in the virus’ reproduction that in lab testing could be effectively targeted with an obsolete antihistamine.
The advance involves two new discoveries. One is that a protein called NS4B is instrumental in binding some of the genetic material, or RNA, and allowing the hepatitis C virus to replicate.
The other is that the erstwhile anti-itching drug clemizole hydrochloride could hinder that protein, resulting in a tenfold decrease in virus replication with no apparent harm to infected liver-like cells. Because the drug has already been used by people, it is eligible for human testing.
“We’re excited about this and we’re actively moving forward toward clinical trials,” said virology expert Jeffrey Glenn, associate professor of gastroenterology and hepatology. He is a co-author of the paper. Other co-authors are postdoctoral scholars Shirit Einav and Doron Gerber,
One of the team’s key discoveries used coin-sized microfluidic chips that shrink tabletop biological experiments down to the tiny scale of nanoliters. The study marked the first time that microfluidic technology has been used to discover a specific drug, said Stephen Quake, professor of bioengineering and co-author of the paper.
In fact, the small team was able to screen more than 1,200 drug candidates and find clemizole in just two weeks, Gerber added.
“That’s just an example of the power of these microfluidics automation technologies that one or two people working together can actually screen very large numbers of compounds,” Quake said. “Big pharmaceutical companies have very large teams and a lot of infrastructure. We’re trying to reinvent the whole process.”
Glenn focused his research on trying to expand the number of drug targets for the disease. After using molecular virology techniques to study the NS4B protein, he and Einav began to suspect it could be such a target.
However, like other proteins associated with cellular membranes, NS4B is difficult to purify in large quantities while retaining the protein’s natural properties and functionality.
But the advantage of microfludics, Quake said, is that the volumes needed for a successful experiment are quite small, meaning that researchers can get by with very little purified, properly functioning protein. What is insufficient for a benchtop experiment is plenty in microfluidics.
Ultimately the researchers discovered that NS4B is an essential player in the virus’ process of binding RNA. This is a necessary step in the virus’ replication process and, through careful observation, the team determined where it binds and how strongly. That led them to realize which kind of drug - a small-molecule compound - could block that interaction.
Should clemizole prove effective in human trials, Glenn said, it could become an essential component in a new class of multidrug treatments for hepatitis C. Other components could be drugs under development elsewhere that target specific enzymes in the virus.
The new research was published in the Sunday online edition of Nature Biotechnology.