PR Newswire, 810 Seventh Avenue, New York, NY 10019 - Friday, 18 October 1996.

Discovered in 1989, the hepatitis C virus (HCV) causes chronic inflammation in the liver. In a majority of patients, HCV establishes a chronic infection that can persist for decades and eventually lead to cirrhosis, liver failure and liver cancer with devastating health consequences. Since its discovery, the magnitude of the virus spread has been determined. Sources at the U.S. Centers for Disease Control and Prevention recently estimated that approximately 3.9 million Americans, or more than one percent of the population, may be infected with HCV. Currently, there is no vaccine available to prevent hepatitis C infection. In addition, the only drug approved for the treatment of hepatitis C, interferon alpha, provides long-term therapeutic benefit to only about 25 percent of patients treated. The magnitude of the hepatitis C epidemic and the lack of effective treatments have spurred a major race to develop useful drugs. Drug companies worldwide are targeting the hepatitis C NS3 protease. To date, pharmaceutical company efforts to identify new drugs for hepatitis C infection based on screening libraries of compounds for activity against hepatitis C have made little apparent progress.

"The NS3 protease of hepatitis C plays a fundamental role in the replication of virus, similar in function to the role that HIV protease plays for the HIV virus, and therefore represents a key target for therapeutic intervention," said Dr. Vicki Sato, Senior Vice President of Research and Development and Chief Scientific Officer of Vertex. "Our experience and success in designing VX-478, a potent, well-tolerated and orally administered HIV protease inhibitor in Phase II clinical trials, make us well-positioned to undertake the challenge of designing a protease inhibitor to treat hepatitis C infection."

Vertex scientists determined the three-dimensional structure of hepatitis C NS3 protease complexed to part of another protein in the viral genome, NS4A, using X-ray crystallography. This biophysical technique determines accurately the position of every atom of the complex. Vertex used X-ray diffraction data with the aid of supercomputer-based modeling and computational techniques to construct a high-resolution (2.5 Angstroms) electron density map of the complex. The map locates the active site of the enzyme, as well as details of the architecture of the NS3/NS4A complex, and the location of a tightly bound metal ion that is important for the enzyme's activity.

"One of the most interesting features of the structure is that NS3 wraps around its cofactor protein, NS4A, in a manner that stabilizes the complex. This architecture explains a wealth of biochemical data characterizing the interaction between the two proteins," said Vertex crystallographer, Dr. Joseph Kim. "In addition, our structural analysis reveals that there is a bound zinc ion located away from active site. This structural element also appears important for enzyme stability and activity."

Dr. John Thomson, Vertex Senior Scientist and Project Head - Hepatitis Research, added, "The structure of the hepatitis C NS3 protease shows, in atomic detail, several unique features of this enzyme that we believe will provide opportunities to accelerate our ongoing efforts to design a potent and specific compound against hepatitis C."

The authors of the Cell paper are Joseph L. Kim, Kurt A. Morgenstern, Chao Lin, Ted Fox, Maureen D. Dwyer, James A. Landro, Steven P. Chambers, William Markland, Christopher A. Lepre, Ethan T. O'Malley, Scott L. Harbeson, Charles M. Rice, Mark A. Murcko, Paul R. Caron and John A. Thomson, all of Vertex, except for Dr. Rice, who is with the Washington University School of Medicine, St. Louis. Dr. Rice is one of the world's leading experts in the molecular biology of hepatitis C and related viruses, and his group led the field in experiments that identified the hepatitis C NS3 protease as an important drug target.

Vertex Pharmaceuticals Incorporated is engaged in the discovery, development and commercialization of novel, small molecule pharmaceuticals for the treatment of diseases for which there are currently limited or no effective treatments. The Company is a leader in the use of structure-based drug design, an approach to drug discovery that integrates advanced biology, biophysics and chemistry. The Company is concentrating on the discovery and development of drugs for the treatment of viral diseases, multidrug resistance in cancer, hemoglobin disorders, inflammation, autoimmune diseases, organ transplant rejection and neurodegenerative diseases.

Copyright (c) 1996/PR NewsWire. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Permissions Desk, PR Newswire, 810 Seventh Avenue, New York, NY 10019.
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