Hepatitis C Protein Is Found, Sparking Race for New Drug

Two biotechnology companies identified the structure of a protein crucial to reproduction of the hepatitis C virus, touching off a contest to find a drug that will do for the common liver malady what protease inhibitors have done for AIDS.

The discovery, published in Friday's issue of the journal Cell, includes two dueling papers by Vertex Pharmaceuticals Inc., of Cambridge, Mass., and Agouron Pharmaceuticals Inc., of La Jolla, Calif. Identifying the protein structure is a major milestone in the international race to design a hepatitis C drug using biotechnology's most elegant tools. More than 8,000 Americans a year die from hepatitis C.

Information is available in the on-line edition of the Journal cell at http://www.cell.com/cell/index.html .

"The starting gun has been fired and the race has begun," says Vertex Chief Executive Officer Joshua Boger.

The three-dimensional structure of the protease, a large winding protein with many nooks and crannies, provides a starting point to design a drug that gums up its works. If the protease is disabled, the hepatitis virus would be unable to reproduce itself and, scientists hope, the disease will be cured. The research is the latest effort to parlay the success of HIV protease inhibitors, which have recently offered new hope to AIDS patients, into other diseases.

The HIV protease structure was published by Merck & Co. scientists in 1989, followed by the common-cold protease by Agouron in 1994 and a herpes-virus protease by several companies this fall. Friday's publication marks the fourth such major discovery, and "highlights a whole new era in antiviral research," says Peter Johnson, chief executive at Agouron.

Identifying a hepatitis C drug will now take at least two or three years of intensive research, Vertex and Agouron said. The companies said they published just enough information about the protease structure to make credible scientific papers, but left out details that might be helpful to competitors, which include research heavyweights such as Chiron Corp. and Merck.

Hepatitis C is "a major public health problem" that affects 3.9 million Americans, according to the American Liver Foundation. Many people show either no symptoms or flulike symptoms, but the disease can progress to cause either liver cancer or cirrhosis of the liver, both of which can be fatal. Rachel Leheny, a biotechnology analyst at Hambrecht & Quist in Manhattan, says an effective drug for the disease could rack up $2 billion to $3 billion a year in sales.

"In the U.S., 1.8% of the population is infected. The only treatment currently available is alpha interferon and it cures only 10%-15% of the people," says Adrian Di Bisceglie, a professor at St. Louis University Medical Center, who edits the quarterly Viral Hepatitis Review. "We badly need a new drug."

He adds that protease-inhibitor research is "the next major area of interest in hepatitis C." But the hepatitis C virus protease is likely to be a more difficult target than the HIV protease, because its working end is "broader and more open," says Agouron's Mr. Johnson. That means it will be trickier to find a small-molecule drug that will wedge firmly into the protease.

While Vertex and Agouron appear to be describing the same protein, the two disagree on one major point. Vertex's paper describes the structure of a smaller protein that nestles into the protease and helps to stabilize it, and Mr. Boger describes that protein as "extraordinarily important" because it provides a possible drug target. But Agouron didn't describe that protein in its paper, because "we feel it is extremely unlikely to be a drug target," Mr. Johnson says. Vertex's Mr. Boger counters that "if they chose not to highlight it in their paper, maybe they don't understand their own structure."


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