Metallodrugs Targeting HCV Protease

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DESCRIPTION (provided by applicant): Alcohol is a high risk factor in hepatitis C virus (HCV) infection and increases the severity of the infection. It has been estimated that 35% of alcohol-dependent people carry HCV. HCV is associated with cirrhosis, liver failure, and hepatocellular cancer, and alcohol exacerbates all of these pathogenic conditions. The major purpose of this application is to create new metallodrug constructs that catalytically and irreversibly destroy the virus in infected cells. HCV is a positive, single-stranded RNA enveloped virus that contains about 10,000 nucleotides that are translated into a single polyprotein of about 3,000 amino acids. A full length negative strand is the intermediate that contains the core, envelope and non-structural protein regions. Substantial sequence variation is caused by hypervariable regions in the envelope region, thus contributing to the difficulty in making robust vaccines and therapeutic drugs. The polyprotein is converted by host and viral proteases into structural and non-structural proteins necessary for viral replication and infection. About 10,000 people die each year in the US as a result of HCV infection. Most hepatitis is caused by HCV that is transmitted through contact with infected blood, sexual contact, or contact between fetus or infant and mother. About 85% of those with acute infections develop chronic infections of HCV. Chronic infection is almost never spontaneously cleared without treatment and alcohol increases the infection. Millions of people worldwide (about 170,000,000 people or 2% of the world's population) are infected and a significant portion of the US population (about 4 million) carry HCV. Current therapy uses a combination of interferon and ribavirin. Treatment is expensive and not very effective. Moreover, it does not clear the virus from the patient. MetalloPharm has novel technology that uses an innovative metallodrug to catalytically inactivate the virus and clear it from the infected cell. New metallodrugs will be made and tested for their ability to inhibit the virus in cell culture assays using human cells infected with HCV replicons, which are subgenomic pieces of HCV. After optimization, selected constructs will be tested for efficacy, toxicity and their pharmacokinetic and biodistribution properties in rodents. PUBLIC HEALTH RELEVANCE: Alcohol and hepatitis C virus (HCV) are a deadly combination. HCV infects about one third of alcoholics. Metallopharm has created novel technology (metallodrugs) that have the potential to clear the virus from infected cells and thereby improve the ineffective and expensive treatment that is currently offered to patients.