Cambridge, MA, January 15, 1998 -- Researchers from Vertex Pharmaceuticals Incorporated have solved the three-dimensional atomic structure of the hepatitis C virus NS3 helicase, an enzyme that plays a key role in viral replication. The achievement is described in a paper, "Hepatitis C Virus NS3 RNA Helicase Domain with a Bound Oligonucleotide: The Crystal Structure Provides Insights into the Mode of Unwinding," published in the January 15, 1998 issue of the journal Structure. The publication follows the presentation of the helicase structure at the Second International Conference on Therapies for Viral Hepatitis in Kona, Hawaii, in December 1997. Vertex is using the structural information to design hepatitis C helicase inhibitors as new antiviral drugs to treat hepatitis C virus (HCV) infection.

"This paper presents for the first time detailed information on the critical interaction between the hepatitis C helicase and viral RNA," said Dr. Joseph L. Kim, Vertex crystallographer and an author of the Structure paper. "The nucleic acid binding site of the helicase enzyme, as well as the previously described nucleoside triphosphate (NTP) binding site, are attractive targets for disrupting this interaction. These two targets, which comprise the active sites of the helicase enzyme, are a focus of our ongoing drug design efforts."

Helicases are enzymes distinguished by their ability to unwind regions of double-stranded RNA or DNA, in preparation for replication or transcription of genetic information. In the case of hepatitis C, the NS3 helicase functions to unwind double-stranded viral RNA complexes. The resulting RNA strands then serve as templates for the synthesis of more RNA or for translation into protein. Alternately, the new RNA may be packaged into new virus particles, which are released from cells to propagate infection.

Vertex scientists determined the three-dimensional structure of hepatitis C NS3 helicase complexed with a single-stranded DNA oligonucleotide 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 computational techniques to construct a high-resolution (2.2 angstroms) electron density map of the complex. The map reveals the nucleic acid-binding site, as well as the previously described ATP-binding site that drives the enzyme's activity, amid three distinct structural domains of the NS3 helicase. The structure yields important clues regarding the mechanism by which helicase enzymes unravel double-stranded nucleic acid helices.

"The atomic structure of the HCV helicase enzyme shows several unique features that we believe will provide opportunities to accelerate our ongoing efforts to design potent and specific drugs against hepatitis C," said Dr. Paul Caron, Vertex biophysicist and also an author of the Structure paper. "In addition to providing information on a key target for therapeutic intervention, the structural data we have unveiled also suggests a possible mechanism of nucleic acid unwinding for this and related helicases. "

"The solution of the HCV helicase structure complements the solution of the three-dimensional atomic structure of another drug target, HCV protease, reported by Vertex researchers in 1996," added Dr. Vicki L. Sato, Senior Vice President of Research and Development and Chief Scientific Officer of Vertex. "Given the combination therapy approach now being advocated and developed for treatment of many viral diseases, pursuing multiple discovery targets against HCV enhances our competitive position in the future market for HCV therapies."

Discovered in 1989, 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. Sources at the U.S. Centers for Disease Control and Prevention (CDC) recently estimated that approximately 3.9 million Americans, or more than one percent of the population, may be infected with HCV. An additional 3-4 million people in Europe and Japan carry the hepatitis C virus. Currently, there is no vaccine available to prevent hepatitis C infection.

Current treatment options for hepatitis C are widely acknowledged to be suboptimal. 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. Recent clinical research results indicate that combination antiviral therapy for HCV patients, in particular interferon alpha plus ribavirin, may improve response rates.

In 1996, Vertex researchers reported solving the structure of hepatitis C protease, another crucial enzyme involved in viral replication, in the journal Cell. That discovery propelled forward a multidisciplinary effort underway to identify small molecule inhibitors of HCV protease. In 1997, Vertex entered a collaboration with Eli Lilly & Co. to design and develop compounds directed against HCV protease. The deal calls for Eli Lilly to provide up to $50 million in research support and other payments, as well as pay Vertex royalties on product sales. Lilly will have worldwide marketing rights.

The authors of the Structure paper are Joseph L. Kim, Kurt A. Morgenstern, James P. Griffith, Maureen D. Dwyer, John A. Thomson, Mark A. Murcko, Chao Lin, and Paul R. Caron, all of Vertex.

Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) 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, autoimmune diseases, inflammatory diseases, and neurodegenerative diseases.