Structure, dynamics, and function of the viroporins Vpu from HIV and p7 from HCV

HIV 病毒孔蛋白 Vpu 和 HCV 病毒 p7 的结构、动力学和功能

• 批准号: 7508672
• 负责人: STANLEY J OPELLA
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7508672
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Bacteria; Binding; Biological; Biological Process; CD4 Antigens; Cell surface; Cells; Cirrhosis; Class; Complex; Cytoplasmic Tail; DNA; Development; Disease; Drug Binding Site; Drug Delivery Systems; Drug user; Ensure; Environment; Family; Flaviviridae; Generations; Genetic; Genome; Goals; HIV; HIV-1; Health; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C virus p7 protein; Hepatocyte; Highly Active Antiretroviral Therapy; Homo; Human; Immune system; Individual; Infection; Interferons; Ion Channel; Kaposi Sarcoma; Label; Lead; Length; Ligand Binding; Liver diseases; Measures; Membrane; Membrane Proteins; Methods; Micelles; Molecular; Molecular Target; Numbers; Opportunistic Infections; Patients; Pharmaceutical Preparations; Phospholipids; Polyubiquitination; Population; Predisposition; Preparation; Primary carcinoma of the liver cells; Property; Proteins; Public Health; RNA Viruses; Regulation; Research; Residual state; Resistance; Resistance development; Retroviridae; Sampling; Side; Solutions; Structure; Structure-Activity Relationship; Subfamily lentivirinae; Tuberculosis; United States; Viral; Viral Proteins; Virion; Virus; Work; anti-hepatitis C; drug development; drug discovery; human morbidity; immune function; liver transplantation; member; molecular mass; mortality; multicatalytic endopeptidase complex; novel; particle; polypeptide; protein structure; receptor; receptor binding; research study; solid state; success; three dimensional structure; trafficking

DESCRIPTION (provided by applicant): Infections with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are among the most significant causes of human morbidity and mortality. Worldwide, there are more than 40 million (HIV) and 170 million (HCV) people infected with these viruses. In the United States, 0.6% (HIV) and 1.7% (HCV) of the population is infected. More than 25% of those infected with HIV are co-infected with HCV (up to 90% of i.v. drug users). Despite the success of highly active anti-retroviral therapy, there is an urgent need to develop entirely new classes of anti-HIV drugs targeted to novel receptors in order to ensure different susceptibilities to the development of resistance. Current therapies for HCV are grossly inadequate, and multiple first-generation anti- HCV drugs are needed. Both HIV-1 and HCV have a viroporin, a small membrane protein with ion channel activity and a potential drug target. The proposed research builds upon recent results, and represents a substantial expansion of our structural studies of membrane proteins. Determining the structures of Vpu (Virus protein "u") from HIV-1 and the p7 protein from HCV are essential in order to understand the molecular mechanisms of their biological activities and to nucleate the discovery of drugs that interfere with these activities. Our NMR methods are particularly well suited for determining the structures of these proteins in their native environment of phospholipid bilayers. And since our approach is unaffected by the molecular mass of the polypeptides, studies of isotopically labeled Vpu bound to unlabeled cellular partners are no more difficult than for Vpu alone. We will explore the application of SAR (structure activity relationships) by NMR to Vpu and p7 as examples of membrane-bound receptors and to identify potential binding sites for drugs. PUBLIC HEALTH RELEVANCE: Infections with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are among the most significant causes of human morbidity and mortality. Worldwide, there are more than 40 million (HIV) and 170 million (HCV) people infected with these viruses. In the United States, 0.6% (HIV) and 1.7% (HCV) of the population is infected. More than 25% of those infected with HIV are co-infected with HCV (up to 90% of i.v. drug users). HIV is a lentivirus in the Retroviridae family. It causes the acquired immunodeficiency syndrome (AIDS) by infecting CD4+ T and other cells of the immune system; the resulting decline of immune functions means that opportunistic infections, such as tuberculosis and Kaposi's sarcoma, and co-infections, such as HCV, have devastating effects on human health. HAART (highly active antiretroviral therapy) is effective in many patients; however, the genetic variability of HIV means that drugs against additional molecular targets are needed to combat resistance that inevitably develops in the course of treating a disease in which the genome of the causative agent is integrated into the host DNA. The proposed studies will provide structural information about Vpu, a key protein in the viral lifecycle that has the potential to be a new target for the development of drugs to treat AIDS. HCV is a member of the Flaviviridae family of enveloped single-stranded RNA viruses that mainly infects hepatocyte. Most HCV infections are persistent and lead to liver diseases, including hepatitis, cirrhosis, and hepatocellular carcinoma. Consequently, HCV is the leading indicator for liver transplantation in the Nation. Current therapy for HCV infections consists of the administration of pegylated interferon and ribivirin and has many limitations; not only is it lengthy, expensive and poorly tolerated, but also it works in only a fraction of cases. The development of effective anti-HCV drugs is a high priority, especially because of the difficulties encountered in treating patients co-infected with HIV and HCV. The proposed studies will provide structural information about p7, a key protein in the viral lifecycle that has the potential to be a new target for the development of drugs to treat hepatitis C.

描述（由申请方提供）：人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）感染是人类发病和死亡的最重要原因之一。全世界有超过4000万人（HIV）和1.7亿人（HCV）感染这些病毒。在美国，0.6%（HIV）和1.7%（HCV）的人口被感染。超过25%的HIV感染者同时感染HCV（高达90%的静脉注射吸毒者）。尽管高活性抗逆转录病毒疗法取得了成功，但迫切需要开发针对新型受体的全新类别的抗HIV药物，以确保对耐药性发展的不同敏感性。目前HCV的治疗方法严重不足，需要多种第一代抗HCV药物。HIV-1和HCV都具有病毒孔蛋白，一种具有离子通道活性的小的膜蛋白和潜在的药物靶点。拟议的研究建立在最近的结果，并代表了我们的膜蛋白的结构研究的实质性扩展。确定来自HIV-1的Vpu（病毒蛋白“u”）和来自HCV的p7蛋白的结构对于理解它们的生物活性的分子机制和使干扰这些活性的药物的发现成为核心是必不可少的。我们的核磁共振方法特别适合确定这些蛋白质在磷脂双层天然环境中的结构。由于我们的方法不受多肽分子量的影响，因此研究同位素标记的Vpu与未标记的细胞伴侣的结合并不比单独的Vpu更困难。我们将探讨应用核磁共振的SAR（构效关系）Vpu和p7作为膜结合受体的例子，并确定潜在的药物结合位点。公共卫生关系：人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）感染是人类发病和死亡的最重要原因之一。全世界有超过4000万人（HIV）和1.7亿人（HCV）感染这些病毒。在美国，0.6%（HIV）和1.7%（HCV）的人口被感染。超过25%的艾滋病毒感染者同时感染了丙型肝炎病毒（高达90%的静脉吸毒者）。HIV是逆转录病毒科中的慢病毒。它通过感染免疫系统的CD 4 + T细胞和其他细胞引起获得性免疫缺陷综合征（艾滋病）;由此导致的免疫功能下降意味着机会性感染，如结核病和卡波西肉瘤，以及合并感染，如HCV，对人类健康具有破坏性影响。HAART（高效抗逆转录病毒疗法）对许多患者有效;然而，HIV的遗传变异性意味着需要针对其他分子靶点的药物来对抗在治疗疾病过程中不可避免地产生的耐药性，其中病原体的基因组整合到宿主DNA中。这项研究将提供有关Vpu的结构信息，Vpu是病毒生命周期中的一种关键蛋白质，有可能成为开发治疗艾滋病药物的新靶点。HCV是主要感染肝细胞的有包膜单链RNA病毒的黄病毒科的成员。大多数HCV感染是持续性的，并导致肝脏疾病，包括肝炎，肝硬化和肝细胞癌。因此，HCV是全国肝移植的主要指标。目前的HCV感染治疗包括聚乙二醇干扰素和利巴韦林的管理，并有许多局限性，不仅是漫长的，昂贵的和耐受性差，而且它的作品只有一小部分的情况下。有效的抗HCV药物的开发是一个高度优先事项，特别是因为在治疗合并感染HIV和HCV的患者时遇到的困难。拟议的研究将提供有关p7的结构信息，p7是病毒生命周期中的一种关键蛋白质，有可能成为开发治疗丙型肝炎药物的新靶点。