Novel Urazole Epoxyquinol Inhibitors of Hepatitis C Virus Replication

Summary Background: Hepatitis C virus (HCV) infects about 200 million people worldwide and frequently leads to cirrhosis, liver failure, and hepatocellular carcinoma. Currently, the best therapy for the treatment of chronic hepatitis C is a combination of pegylated interferon (PEG-IFN) and ribavirin. While the sustained virologic response (SVR) rate approaches 80% for patients with genotypes 2 and 3, the SVR rate is limited to about 45% for those with HCV genotype 1, which accounts for about 75% of all cases of HCV in the United States. Furthermore, interferon is parenteral, has an unfavorable side-effect profile, and its use requires frequent monitoring for toxicity, ultimately causing 20% of patients to discontinue therapy. The identification of more effective and better tolerated agents is therefore a high priority.

Inventions: The identification of a novel set of compounds that regulate HCV replication. Lead compounds have IC50’s of approximately 3 uM, with cytotoxic effects above 10 uM.

In addition to the lead compounds discovered in this technology, the researchers also developed a novel high-throughput screening assay (HTS). The assay measures both the level of HCV replication and cell viability. By performing a reporter gene assay in parallel with a cell viability assay, one can efficiently screened out false positives by determining either significant decreases or increases in cell titer.

Applications Advantages: The compounds identified by these screens could potentially be used not only for medicinal effect but also as a productive approach to the characterization of key viral-host interactions critical to viral replication. Using the HTS screening assay, a large library of well characterized, known biologically active compounds or novel compounds can be screened using automated technology. The current discovery of regulators of HCV replication from the DOS Set demonstrates that the HTS assay is universally applicable to compound libraries beyond those consisting of known bioactive compounds.

Applications: Treatment of individuals with Hepatitis C virus (HCV) infection.

Publications: Identification of novel epoxide inhibitors of hepatitis C virus replication using a high-throughput screen. 2007. Antimicrobial Agents Chemotherapy, 51(10):3756-9.

A cell-based, high-throughput screen for small molecule regulators of hepatitis C virus replication. 2007. Gastroenterology, 132(1):311-20. For Further Information Please Contact the Director of Business Development Laura Brass Email: [email protected] Telephone: (617) 495-3067

Inventor(s): Schreiber, Stuart L.

Type of Offer: Licensing



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