Anti HCV Protease Activities of Metalloporphyrins

描述（由申请人提供）： 丙型肝炎（HCV）是肝硬化的主要原因，在世界范围内发病率相当高。目前慢性HCV感染的治疗是α-干扰素（IFN）和利巴韦林（RBV）24-48周，以及批准的蛋白酶抑制剂，这取决于HCV基因型。不幸的是，大约一半的治疗患者在治疗后未能实现持续的病毒根除。密集的研究集中在开发新的直接作用的抗HCV药物，以补充和改善目前的治疗。虽然第一代HCV蛋白酶抑制剂是一个值得注意的进步，但我们必须继续寻求新的，更有效的抗病毒药物。我们小组和其他人最近的发现表明，血红素代谢的前体和产物是直接作用的抗病毒剂。金属卟啉（MP）如血红素和血红素氧化产物如胆绿素有效地抑制HCV NS 3/4a蛋白酶。这些令人兴奋的发现提高了MP可用作治疗慢性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，并且在生活中大量存在。一些MP如血红素和锌原卟啉已经被批准用于人类的选择性治疗作用，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在HCV基因型的广泛杀病毒谱中抑制NS 3/4a蛋白酶。MP还恢复了I型干扰素的先天免疫信号转导后，病毒蛋白酶的抑制，这表明他们将提供额外的好处先天免疫系统识别，宿主免疫和病毒清除。本申请的总体假设是， 血红素前体和血红素氧化的选择性产物是HCVNS 3/4a蛋白酶的有效抑制剂。具体目的有三：1）研究金属卟啉类化合物的体外抗HCV NS 3/4a蛋白酶活性。2)我们将研究MP对HCV复制的抑制作用和MP的细胞内活性。3）研究金属卟啉的体内抗HCV活性。我们工作的长期目标是确定这类化合物的最佳抗病毒剂，以便我们可以改善慢性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。本申请的直接目标是表征MP的抗病毒作用，以及建立 这些化合物用于人类治疗用途的可行性。

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.