Metallodrugs Targeting HCV Protease

靶向 HCV 蛋白酶的金属药物

• 批准号: 7747145
• 负责人: Ada S Cowan
• 金额: $ 22.2万
• 依托单位: METALLOPHARM, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7747145
• 关键词: Acute; Alcohol dependence; Alcohols; Amino Acids; Animal Model; Binding; Biodistribution; Biological Assay; Blood; Cell Culture Techniques; Cells; Cessation of life; Chemistry; Chronic; Chronic Hepatitis C; Cirrhosis; Complementarity Determining Regions; Dose; Drug Kinetics; Drug resistance; Fetus; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatocyte; Homebound Persons; Human; Immune response; Infant; Infection; Interferons; Lead; Length; Liver; Liver Failure; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Metals; Mothers; Nucleotides; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Polyproteins; Population; Primary carcinoma of the liver cells; Property; Protein Region; RNA; Replicon; Ribavirin; Risk Factors; Rodent; Severities; Structural Protein; Testing; Therapeutic; Toxic effect; Translating; Variant; Viral; Viral hepatitis; Virus; alcohol abuse therapy; anti-hepatitis C; design; efficacy testing; high risk; improved; inhibitor/antagonist; innovation; new technology; novel; problem drinker; public health relevance; therapeutic target; therapeutic vaccine

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.

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，并增加感染的严重程度。据估计，35%的酒精依赖者携带HCV。HCV与肝硬化、肝功能衰竭和肝细胞癌有关，酒精会加重所有这些致病性疾病。该应用的主要目的是创建新的金属药物结构，其催化地且不可逆地破坏感染细胞中的病毒。HCV是一种阳性单链RNA包膜病毒，含有约10，000个核苷酸，这些核苷酸被翻译成约3，000个氨基酸的单个多聚蛋白。全长负链是包含核心、包膜和非结构蛋白区域的中间体。大量的序列变异是由包膜区中的高变区引起的，因此导致难以制备稳健的疫苗和治疗药物。多蛋白被宿主和病毒蛋白酶转化为病毒复制和感染所必需的结构和非结构蛋白。在美国，每年约有10，000人死于HCV感染。大多数肝炎是由HCV引起的，通过接触受感染的血液，性接触或胎儿或婴儿与母亲之间的接触传播。约85%的急性感染者发展为慢性HCV感染。慢性感染几乎从来没有自发清除没有治疗和酒精增加感染。全世界有数百万人（约170，000，000人或世界人口的2%）被感染，美国人口的很大一部分（约400万）携带HCV。目前的治疗使用干扰素和利巴韦林的组合。治疗费用昂贵，而且效果不佳。此外，它不能从患者身上清除病毒。MetalloPharm拥有一项新技术，该技术使用一种创新的金属药物来催化病毒并将其从受感染的细胞中清除。新的金属药物将被制造出来，并在细胞培养试验中测试它们抑制病毒的能力，所述细胞培养试验使用被HCV复制子感染的人类细胞，所述复制子是HCV的亚基因组片段。优化后，将测试所选构建体在啮齿动物中的功效、毒性及其药代动力学和生物分布特性。 公共卫生相关性：酒精和丙型肝炎病毒（HCV）是一种致命的组合。HCV感染约三分之一的酗酒者。Metallopharm创造了一种新技术（金属药物），有可能从受感染的细胞中清除病毒，从而改善目前为患者提供的无效和昂贵的治疗。