Schering-Plough Researchers Identify Promising Drug Targets in Hepatitis C  Virus

Jules Levin,NATAP

MADISON, N.J., Oct. 28 /PRNewswire/ -- In a potentially major step against a lethal infectious disease, scientists at Schering-Plough Research Institute have identified the structure of an enzyme complex that is essential to replication of the hepatitis C virus (HCV).

In an article published in the November issue of Structure, Schering-Plough researchers report the three-dimensional structure of a multi-functional HCV protein known as NS3. Protease and helicase activities of NS3 are required for viral maturation and replication. The article builds on an earlier report published in the October issue of Nature Structural Biology, in which company researchers first identified the structure of NS5B, an RNA polymerase that produces copies of the HCV RNA genome for packaging into infectious virus particles. This work completes Schering-Plough's effort to determine the molecular structure of all key enzymes of the hepatitis C virus. These unique, virally encoded proteins are essential in the life cycle of the hepatitis C virus and constitute promising targets for drug interaction.

"Determining the three-dimensional structure of the HCV helicase, protease and polymerase allows us to use advanced structure-based drug design methods to complement medicinal chemistry," said Cecil B. Pickett, Ph.D., executive vice president of discovery research, Schering-Plough Research Institute. "By finding multiple ways to target HCV replication, we've opened the door to the discovery of new drugs that may be more effective than any therapies currently available."

Schering-Plough is the leader in structural biology of HCV. Company researchers are using their knowledge of how the HCV helicase, protease and polymerase are constructed to design antiviral agents that can inhibit the enzyme activities required for viral maturation and replication. Once developed, these inhibitors, either alone or in combination with existing therapies, may be effective in eradicating the hepatitis C virus in patients chronically infected with the disease.

"The structure of the HCV RNA polymerase provides an important piece of the puzzle for virologists trying to decipher the mechanism of HCV replication," Pickett noted. "Moreover, the structure of the HCV helicase/protease complex provides new insights into its function, which were not anticipated from what was previously known about the structures of the isolated protease and helicase domains."

Some 4 million Americans are infected with the hepatitis C virus and approximately 70 percent of infected patients go on to develop chronic liver disease, according to the Centers for Disease Control and Prevention (CDCP). Hepatitis C infection contributes to the deaths of an estimated 8,000 to 10,000 Americans each year. This toll is expected to triple by the year 2010 and exceed the number of annual deaths due to AIDS, according to the CDCP. The American Liver Foundation has reported that liver failure due to hepatitis C infection is the leading cause of liver transplants in the United States.

In Europe, 1 percent to 2 percent of the general population is chronically infected with the hepatitis C virus. According to a study conducted by the World Health Organization (WHO), as many as 5 million Europeans are chronically infected with the disease.

Schering-Plough Research Institute is the pharmaceutical research and development arm of Schering-Plough Corporation (NYSE: SGP), a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.