Technology

Waging War on Hepatitis C


Many viruses have figured out ways to elude the body's protective system. One of the cleverest is the hepatitis-C virus. In scores of millions of infected people, the bug does its damage by making trillions of new viruses a day, years after year.

The eventual result often is liver failure or cancer. The cost to the health-care system: an estimated $20 billion to $50 billion a year in the U.S. alone.

But while the virus' ability to hide from the body's defenses is well known, the details of its cunning strategy were a mystery -- until now. The answer is not only a scientific surprise; it also has important medical implications.

Experimental drugs now in clinical trials will be far more effective against the virus than anyone had expected. "The drugs have shown such a tremendous effect because the virus is getting a double whammy," explains Dr. Stanley Lemon, professor of microbiology, immunology, and internal medicine at the University of Texas Medical Branch at Galveston. He's one of the leaders of the effort to decipher the mechanism.

ALARMING DISCOVERY. Here's why. Like most viruses, the hepatitis-C bug commandeers the host's cellular machinery to make copies of itself. For instance, it uses cells' protein factories to make proteins that will become the virus' coat. But before these proteins can be assembled into the coat, they must be sliced and diced in several key places. That's the job of a viral enzyme called protease.

When Lemon and his colleagues set out to learn how hepatitis C evaded the body's defenses, they discovered that the enzyme was doing another, unexpected, job. "It was a surprise to find that the protease of the virus was involved in blocking the innate immune system response," he says. Lemon's team employed some elegant scientific sleuthing to solve the mystery. Turns out that "the protease targets two cellular signaling molecules at the very beginning of the immune process," he says.

Think of the immune system as having a built-in burglar alarm. Cells roam the body equipped with little detectors, or receptors, on their surface. These receptors seek out and attach to foreign invaders, such as viruses. Once the receptor finds such an invader, it sends out an alarm, mobilizing the immune system to attack the invader.

In the case of the hepatitis-C virus, the cells successfully identify them as foreign invaders. But the alarm signal they try to send doesn't get through. The viral protease, Lemon discovered, chops up two crucial molecules that carry the alarm. So even though the "burglar" is detected, the alarm never gets sent to the immune system's police station.

ONE LOCK, MULTIPLE KEYS. This ability to evade the immune system has two enormous consequences for drug development. First, a drug that successfully targets the viral protease will be unusually effective. That's because it would not only hit the virus directly, but would also restore the immune system, which is then able to launch its own attack.

But such drugs are difficult to design. That's a direct result of the viral protease enzyme's unusual ability to have several targets -- the viral proteins it cleaves to ensure viral reproduction, and the immune system signaling proteins.

Most enzymes work only on one target. When scientists look at their three-dimensional shape, these normal enzymes typically have a deep indentation or pocket. The target protein fits into that pocket like a key into a lock.

The hepatitis-C protease enzyme, however, has figured out how to work on several targets. "There are multiple keys for that one lock," explains Lemon. As a result, the lock -- that is, the pocket -- must be exceptionally versatile.

HUGE PAYOFF POTENTIAL. Indeed, when scientists at Vertex Pharmaceuticals (VRTX) in Cambridge, Mass., figured out the shape of the enzyme in 1997, they discovered that it has an unusually shallow pocket. That, in turn, made it hard to design a drug that fits in the "lock." When the shape of the enzyme was discovered, "we said: 'Oh, boy, that will be a tough problem,'" recalls Vertex Chief Executive Josh Bogor.

It took the company years to design a drug that could fit in the pocket, thus disabling the viral enzyme. "It turned out to be an excruciating, atom-by-atom exercise," says Boger.

The potential payoff, however, is huge. Results of a small trial with the drug, announced by Vertex in early February, were astonishing. After four weeks of treatment with the drug, in combination with the current standard treatment, the hepatitis-C virus became undetectable in all of the 12 patients.

The hope, of course, is that the drug's dual effect -- attacking the virus and restoring the immune system response -- will bring an actual cure for patients infected with the virus. That would be a major advance from current treatment, which uses an immune system booster called interferon, a treatment that is often debilitating. It takes many months to even have a chance of working, and fails in a large number of cases.

UNFORESEEN SIDE EFFECTS? Vertex isn't the only company in the hunt with a protease inhibitor for hepatitis C. Schering-Plough (SGP) has one in Phase II clinical trials, and on Jan. 30 reported that it had gotten fast-track designation from the FDA. GlaxoSmithKline (GSK) is said to be working on one as well. Boehringer Ingelheim was actually in the lead at one point, but it had to stop development of its promising candidate because of side effects.

Another possible stumbling block: The new Vertex drug could still fail in upcoming trials, due to unforeseen side effects. But based on the latest results, it is currently the best hope. Wall Street has taken notice. Vertex shares now cost around $38, up from $8.83 last April.

This tale may be a rare case of a drug working far better than anyone expected -- all thanks to the hepatitis-C virus' remarkable ability to shut off the immune system.


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