Hepatitis C Achilles Heel Found

Drugs Now In Pipeline May Shorten, Ease Hepatitis C Treatment

From the WebMD Archives

April 17, 2003 -- The central mystery of hepatitis C now is solved. A new finding promises more effective, shorter, and easier hepatitis C treatments.

What Michael Gale Jr., PhD, and colleagues discovered is how hepatitis C virus establishes lifelong infection. They found that the virus makes a key that lets it turn off a cell's anti-virus machinery. And they found that a type of drug -- already in development by several companies -- robs the virus of this key. Without it, the anti-viral machinery comes to life. It churns out a chemical called interferon that rids the cell of the hepatitis C virus.

"The beauty of [this type of drug] is it can clear persistently infected cells," Gale tells WebMD. "The cells rid themselves of hepatitis C virus within an average time of four to five days."

Gale and colleagues at University of Texas Southwestern Medical Center, Dallas, wondered why hepatitis C virus is able to cause long-lasting infection. Most viruses can't do that. Gale guessed that hepatitis C virus must somehow disable a crucial immune response -- some part of the innate immune system that's part of almost every cell in the body.

A crucial clue came from the McGill University lab of John Hiscott, PhD, in Montreal. Hiscott was studying the molecular switches that trigger interferon release inside a cell. One of these triggers is called interferon regulatory factor 3 or IRF-3. He gave Gale some IRF-3 to work with.

Gale's lab then found that a protein made by hepatitis C virus blocks IRF-3.

"By blocking it completely, hepatitis C virus prevents the cell from mounting an immune response," Gale says. "That lets the virus get a foothold soon after infection. Once it has this foothold, it never lets go."

The IRF-3 blocking protein is an enzyme called protease. Like hepatitis C virus, the AIDS virus also makes a kind of protease. Drugs that disable protease -- protease inhibitors -- revolutionized AIDS treatment. Several inhibitors of hepatitis C protease are now in the drug pipeline. Schering-Plough Corp. gave Gale some of its experimental drug, which he calls SCH6.

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"We found that SCH6 not only inhibits hepatitis C protease, but also allows restoration of this cellular immune response," Gale says. "We could restore the ability of infected cells to respond to the virus, and naturally clear the virus on its own."

There's more good news. Gale's lab worked with genotype 1. It's the most common type of hepatitis C in the U.S. -- and the hardest kind to treat. Yet the protease inhibitor knocked it out.

By attacking the virus and also turning on antiviral immunity, hepatitis C protease inhibitors would have a dual action. And there's likely a third kind of action. Protease inhibitors likely would make current interferon treatments work better, at lower and less toxic doses. That's an exciting idea to Leslye Johnson, PhD, chief of the enteric and hepatic diseases branch at the National Institute of Allergy and Infectious Diseases.

"If a compound like this goes forward into clinical trials, it has the potential for dual activities and may work better than what's out there now," Johnson tells WebMD. "It might also allow people to use decreased doses of interferon. This finding opens new possibilities that are important for drug development. What it says for patients is that a hepatitis C protease inhibitor, as long as it is safe and everything else, could have multiple ways of getting rid of the virus. That is really the bottom line."

At least three drug companies are working on hepatitis C protease inhibitors. Farthest along appears to be BILN 2061 from Boehringer Ingelheim Pharma. It's already being tested in humans. The Schering-Plough product is not yet ready for human tests, says Schering spokesman Robert Consalvo.

Gale's findings appear in the April 17 issue of the online journal Sciencexpress. Also appearing in the same issue is an article by Hiscott's lab, offering new insights into how viruses trigger a cells antiviral immune response. That finding may lead to drugs effective not only against hepatitis C, but all viruses.

WebMD Health News

Sources

SOURCES: Sciencexpress, April 17, 2003. Michael Gale Jr., PhD, University of Texas Southwestern Medical Center, Dallas. Leslye Johnson, PhD, chief, enteric and hepatic diseases branch, National Institute of Allergy and Infectious Diseases. Robert Consalvo, director of external communications, Schering-Plough Corp.
© 2003 WebMD, Inc. All rights reserved.

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