Novel Engineered Synthetic Metallodrugs Directed Against HCV

针对 HCV 的新型工程合成金属药物

• 批准号: 7220133
• 负责人: Donna T Palmer
• 金额: $ 15.67万
• 依托单位: METALLOPHARM, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7220133
• 关键词: Acute; Alcohol dependence; Alcohols; Amino Acids; Binding; Binding Sites; Biodistribution; Biological Assay; Blood; Cells; Chronic; Cirrhosis; Complementarity Determining Regions; Condition; Cultured Cells; Data; Drug Design; Drug Formulations; Drug Kinetics; Elements; Endopeptidases; Engineering; Evaluation; Fetus; Figs - dietary; Goals; Guanosine Monophosphate; Hepatitis; Hepatitis C; Hepatitis C virus; Human; In Vitro; Infant; Infection; Infectious hepatitides; Interferons; Internal Ribosome Entry Site; Ions; Kinetics; Length; Ligand Binding; Liver; Liver Failure; Metal Binding Site; Metals; Mothers; Nucleotides; Patients; Penetration; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Polyproteins; Population; Primary carcinoma of the liver cells; Property; Protein Region; Purpose; RNA; Replicon; Ribavirin; Risk Factors; Rodent; Safety; Severities; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Specificity; Structural Protein; Tertiary Protein Structure; Testing; Thermodynamics; Translating; Variant; Viral; Virus; alcohol abuse therapy; concept; improved; innovation; metalloenzyme; new technology; novel; problem drinker; programs; research clinical testing; synthetic construct; therapeutic vaccine; viral RNA

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 their pharmacokinetic and biodistribution properties in rodents. 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.

描述（由申请人提供）：酒精是丙型肝炎病毒（HCV）感染的高危因素，会增加感染的严重程度。据估计，35%的酒精依赖者携带丙型肝炎病毒。丙型肝炎病毒与肝硬化、肝功能衰竭和肝细胞癌有关，而酒精会加重所有这些致病性疾病。这项应用的主要目的是创造新的金属药物结构，催化和不可逆地破坏感染细胞中的病毒。