Metallodrugs Targeting HCV Protease

描述(由申请人提供)：酒精是丙型肝炎病毒感染的高危因素，并增加了感染的严重性。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变、肝功能衰竭和肝细胞癌有关，而酒精会加剧所有这些致病条件。这一应用的主要目的是创造新的金属药物结构，以催化和不可逆转地摧毁感染细胞中的病毒。丙型肝炎病毒是一种阳性的单链RNA包膜病毒，包含约10,000个核苷酸，这些核苷酸被翻译成一个约3,000个氨基酸的多蛋白。全长负链是包含核心、包膜和非结构蛋白区域的中间产物。大量的序列差异是由包膜区域的高变区引起的，因此增加了制造强效疫苗和治疗性药物的难度。该多聚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蛋白和非结构蛋白。在美国，每年约有1万人死于丙型肝炎病毒感染。大多数肝炎是由丙型肝炎病毒引起的，它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而传播。约85%的急性感染者会发展为慢性丙型肝炎病毒感染。如果不进行治疗，慢性感染几乎永远不会自发消失，酒精会增加感染。全世界有数百万人(约1.7亿人或世界人口的2%)感染了丙型肝炎病毒，其中很大一部分美国人(约400万人)携带丙型肝炎病毒。目前的治疗方法是干扰素和利巴韦林的组合。治疗费用昂贵，而且效果不是很好。此外，它不会清除患者体内的病毒。金属制药公司拥有一项新技术，它使用一种创新的金属药物来催化灭活病毒，并将其从受感染的细胞中清除。将制造新的金属药物，并在细胞培养试验中测试它们抑制病毒的能力，方法是使用感染丙型肝炎病毒复制子的人类细胞，复制子是丙型肝炎病毒的亚基因组片段。优化后，将测试选定的构建物的有效性、毒性以及它们在啮齿动物体内的药代动力学和生物分布特性。 与公共卫生相关：酒精和丙型肝炎病毒(丙型肝炎病毒)是致命的组合。大约三分之一的酗酒者感染丙型肝炎病毒。金属药物创造了新的技术(金属药物)，有可能从感染细胞中清除病毒，从而改善目前提供给患者的无效和昂贵的治疗方法。

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.