Anti HCV Protease Activities of Metalloporphyrins

金属卟啉的抗HCV蛋白酶活性

• 批准号: 8666517
• 负责人: WARREN N SCHMIDT
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666517
• 关键词: Adverse effects; Antiviral Agents; Antiviral Response; Antiviral Therapy; Bilirubin; Biliverdin reductase; Biliverdine; Binding; Cell Culture Techniques; Cell Respiration; Cells; Characteristics; Chlorophyll; Chronic Hepatitis C; Cirrhosis; Data; Development; Electron Transport; Enzymes; Generations; Genotype; Goals; HIV; Health; Health Benefit; Heme; Hemoglobin; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Icterus; Immune; Immune system; Immunity; Immunosuppressive Agents; In Vitro; Inhibitory Concentration 50; Interferon Type I; Interferon-alpha; Interferons; Life; Life Cycle Stages; Liver diseases; Medical; Metabolism; Metalloporphyrins; Morbidity - disease rate; Mus; Newborn Infant; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Porphyrias; Protease Inhibitor; Replicon; Research; Research Project Grants; Ribavirin; Signal Pathway; Signal Transduction; Specificity; Staging; Tetrapyrroles; Therapeutic; Therapeutic Uses; Toxic effect; Treatment Protocols; Veterans; Viral; Virus; Virus Replication; Work; anti-hepatitis C; cost; heme oxygenase-1; improved; in vitro activity; in vivo; inhibitor/antagonist; liver transplantation; novel; oxidation; pathogen; resistance mutation; social; standard care; viral resistance; virucide; zinc protoporphyrin

DESCRIPTION (provided by applicant): Hepatitis C (HCV) is a major cause of cirrhosis and considerable morbidity worldwide. Current therapy for chronic HCV infection is alpha-interferon (IFN) and ribavirin (RBV) for 24-48 weeks, together with an approved protease inhibitor, depending on HCV genotype. Unfortunately, about half of all treated patients fail to achieve sustained viral eradication after therapy. Intense research has focused on development of new direct-acting anti-HCV drugs to supplement and improve present therapy. Although the first generation of HCV protease inhibitors is a noticeable step forward, it is imperative that we continue to pursue new, more effective antivirals agents. Recent findings from our group and others indicate that precursors and products of heme metabolism are direct acting antiviral agents. Metalloporphyrins (MPs) such as heme and heme oxidation products such as biliverdin potently inhibit HCV NS3/4a protease. These exciting findings raise the possibility that MPs could be used as novel, yet natural antiviral therapeutic drugs for treatment of chronic HCV infection. As a group, MPs are inexpensive, have minimal toxicity, are easy to isolate and prepare, and are abundant in life. Some MPs such as heme and Zinc protoporphyrin have already been approved for selective therapeutic actions in humans such as the porphyrias and jaundice of the newborn. Mechanistically, our data indicate that specific MPs inactivate the NS3/4a protease across a broad virucidal spectrum of HCV genotypes. MPs also restore innate immune signaling for type I interferons after inhibition by viral protease suggesting that they will provide additional benefits for innate immune system recognition, host immunity, and viral clearance. The overall hypothesis of this application is that heme precursors and selective products of heme oxidation are potent inhibitors of the HCV NS3/4a protease. There are three Specific Aims: 1) We will characterize the anti-HCV NS3/4a protease activity of Metalloporphyrins in vitro. 2) We will study MP inhibition of HCV replication and MP intracellular activities in vitro and 3) Study the anti-HCV activities of metalloporphyrins in vivo. The long term goal of our work is to identify the best antiviral agents of this class of compounds such that we can improve treatment regimens for chronic HCV infection and reduce the medical and social burden of HCV end stage liver disease for US veterans. The immediate goals of this application are to characterize the antiviral actions of MPs as well as establish the feasibility of these compounds for therapeutic use in humans.

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