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.

描述（由申请人提供）： 丙型肝炎 (HCV) 是肝硬化的主要原因，在全世界范围内发病率很高。目前慢性 HCV 感染的治疗方法是使用 α-干扰素 (IFN) 和利巴韦林 (RBV)，持续 24-48 周，并结合批准的蛋白酶抑制剂，具体取决于 HCV 基因型。不幸的是，大约一半的接受治疗的患者在治疗后未能实现持续的病毒根除。深入的研究集中在开发新的直接作用抗 HCV 药物以补充和改进现有疗法。尽管第一代 HCV 蛋白酶抑制剂是一个显着的进步，但我们仍然必须继续寻求新的、更有效的抗病毒药物。我们小组和其他人的最新研究结果表明，血红素代谢的前体和产物是直接作用的抗病毒剂。血红素等金属卟啉 (MP) 和胆绿素等血红素氧化产物可有效抑制 HCV NS3/4a 蛋白酶。这些令人兴奋的发现提出了 MP 可以用作治疗慢性 HCV 感染的新型天然抗病毒治疗药物的可能性。作为一个群体，MP价格低廉，毒性最小，易于分离和制备，并且在生活中丰富。血红素和原卟啉锌等一些 MP 已被批准用于人类的选择性治疗作用，例如新生儿的卟啉症和黄疸。从机制上讲，我们的数据表明，特定的 MP 可以使 NS3/4a 蛋白酶在广泛的 HCV 基因型杀病毒谱中失活。 MP 在被病毒蛋白酶抑制后还能恢复 I 型干扰素的先天免疫信号，这表明它们将为先天免疫系统识别、宿主免疫和病毒清除提供额外的好处。该应用程序的总体假设是 血红素前体和血红素氧化的选择性产物是 HCV NS3/4a 蛋白酶的有效抑制剂。有三个具体目标： 1) 我们将表征金属卟啉的体外抗 HCV NS3/4a 蛋白酶活性。 2）我们将在体外研究MP对HCV复制的抑制和MP细胞内活性；3）在体内研究金属卟啉的抗HCV活性。我们工作的长期目标是确定此类化合物的最佳抗病毒药物，以便我们能够改善慢性 HCV 感染的治疗方案，并减轻美国退伍军人 HCV 终末期肝病的医疗和社会负担。该应用程序的直接目标是表征 MP 的抗病毒作用并建立 这些化合物用于人类治疗用途的可行性。