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Vertex Pharmaceuticals receives United States patent covering assay technology to accelerate drug discovery targeting hepatitis C protease.

Vertex Pharmaceuticals, Inc. (Cambridge, MA; 617-577- 6614) announced that it has received a patent from the United States Patent and Trademark Office for a novel technology to screen compounds for activity against hepatitis C virus protease, using a cell- based assay. The invention is a proprietary tool that can be used to accelerate the discovery of hepatitis C virus protease inhibitors for the treatment of hepatitis C virus infection, and is broadly applicable for drug discovery against other protease enzyme targets as well. The Patent Number is 6,117,639.

To date, efforts to grow hepatitis C virus robustly and reproducibly in cultured cells, in the test tube or in an animal model have not been successful. This has hampered efforts industry-wide to screen compounds for direct activity against hepatitis C virus, especially hepatitis C virus protease inhibitors. Hepatitis C virus infection is recognized as a major threat to public health, and no drugs exist that directly and potently block hepatitis C virus viral replication.

"Working together, our virology and cell biology groups developed a way to measure hepatitis C virus protease activity in a cell-based assay," said Vicki Sato, PhD, senior vice president of research and development and chief scientific officer of Vertex. "Using recombinant DNA techniques, our researchers have created a fusion protein that, when cut by the hepatitis C NS3-4A serine protease, will alter expression of a reporter gene in a highly quantifiable way. This new assay has made it possible to rapidly screen for compounds that may have direct antiviral activity in a cellular environment. Already, we have been able to advance several potent small molecule hepatitis C virus protease inhibitors into pharmacokinetic evaluation, and we could select a drug development candidate as early as 2001."

The hepatitis C NS3-4A serine protease is a virally encoded enzyme generally believed to be essential for replication of hepatitis C virus. Vertex researchers solved the three-dimensional atomic structure of hepatitis C virus protease and reported the results in the journal Cell in 1996. Vertex is collaborating with Eli Lilly and Co. (Indianapolis, IN; 317-261-2000) to discover, develop, and commercialize hepatitis C virus protease inhibitors for the treatment of hepatitis C virus infection. As part of ongoing discovery efforts, Vertex is focused on creating novel assays and techniques to help evaluate potential hepatitis C virus protease inhibitors.

Hepatitis C virus causes inflammation of the liver, which may lead to cirrhosis, liver failure, and liver cancer. Approximately 2.7 million people in the United States are chronically infected with the hepatitis C virus, although many are currently undiagnosed. According to the Centers for Disease Control, hospitalization and death rates due to hepatitis C virus are projected to triple from current levels over the next 10 to 15 years.

Vertex's United States Patent 6,117,639 claims a novel method for determining activity of inhibitory drug candidates against a protease. Vertex's method uses a multi-domain fusion protein comprised of a protease cleavage site and is used to monitor protease activity in a cell via a reporter gene expression system. In the presence of a protease, such as the hepatitis C NS3-4A serine protease, the expression of a reporter gene is significantly reduced. As a result, Vertex can measure the activity of an hepatitis C virus protease inhibitor by the inhibitor's ability to increase the expression of the reporter gene in the presence of that protease. The claimed method is applicable to the discovery of chemical compounds targeting any protease.

Proteases function by cleaving and activating proteins, and play an important role in the regulation of numerous biological processes, including viral replication and activation of the immune response. Proteases have been implicated as contributors to several diseases, including Alzheimer's disease, hypertension, cancer and viral infections. There are numerous examples of marketed drugs that achieve a therapeutic effect by inhibiting protease activity, including HIV protease inhibitors for the treatment of HIV and AIDS, and angiotensin converting enzyme inhibitors for the treatment of hypertension.

"In addition to the hepatitis C NS3-4A serine protease, this patent broadly applies to other proteases, including those which may be the subject of Vertex drug discovery efforts. As part of our chemogenomics approach to drug discovery, we are seeking to develop proprietary technologies that we can integrate into our drug discovery platform, with particular emphasis on technologies that enhance our ability to pursue drug design across families of related protein targets," said Sato.

Vertex's approach to drug discovery, termed "chemogenomics," seeks to capitalize on the emergence of large amounts of genomic information by combining medicinal chemistry and molecular biology to identify and describe many of the possible drug candidates for a drug target or group of targets. As part of this approach, Vertex is pursuing a strategy of parallel drug design in gene families, which are groups of genes with similar sequences that code for structurally similar proteins. Vertex's most advanced efforts in parallel drug design are in the caspase, kinase and protease gene families. Proteases are of strong interest because of the structural similarity among specific proteases, the proven medical value of blocking protease activity with small molecule inhibitors, and the role that proteases play in a range of diseases.

The inventors of the patent are Drs. Thomas Hoock, Ann Kwong, and Ursula Germann, all of Vertex.

Vertex discovers, develops and markets small molecule drugs t hat address major unmet medical needs. Vertex has seven drug candidates in clinical development to treat viral diseases, inflammation, cancer, autoimmune diseases and neurological disorders. Vertex has created its pipeline using a proprietary, information-based approach to drug design that integrates multiple technologies in biology, chemistry and biophysics, aimed at increasing the speed and success rate of drug discovery. Vertex's first approved product is Agenerase (amprenavir), an HIV protease inhibitor, which Vertex co-promotes with Glaxo Wellcome.
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Comment:Vertex Pharmaceuticals receives United States patent covering assay technology to accelerate drug discovery targeting hepatitis C protease.
Publication:BIOTECH Patent News
Article Type:Brief Article
Geographic Code:1USA
Date:Oct 1, 2000
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