PATHOGENIC PROTEIN INTERACTIONS

致病性蛋白质相互作用

• 批准号: 8363556
• 负责人: Vivian Cody
• 金额: $ 0.18万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363556
• 关键词: AIDS/HIV problem; Antiviral Agents; Cervical; Collaborations; Complex; DNA Primase; DNA biosynthesis; Data; Excision; Funding; Generations; Genome; Grant; Herpesviridae; Highly Active Antiretroviral Therapy; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Imiquimod; Immune; Immune system; Infection prevention; Lesion; Malignant Neoplasms; Mutation; National Center for Research Resources; Patients; Prevention; Principal Investigator; Proteins; Reliance; Research; Research Infrastructure; Resources; Sexually Transmitted Diseases; Source; Structure; Therapeutic; Topoisomerase; Type I DNA Topoisomerases; United States National Institutes of Health; Virus; cost; helicase; immunological intervention; inhibitor/antagonist; malignant mouth neoplasm; small molecule; success; weapons

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Human papillomavirus (HPV) is the most common sexually-transmitted infections, and the cause of nearly all cervical and anogenital, and over half of oral cancers. Current HPV treatment is by lesion removal or through immunological intervention (imiquimod as an immune stimulant, or the HPV vaccines to prevent infection of the most common HPVs). While antiviral agents have been developed against many types of viruses, to date no true antivirals are available against HPV. With the heavy reliance on the immune system for HPV treatments/prevention, HPV infections and cancers remain a major problem for HIV/AIDS patients, even after HAART treatment. A true HPV antiviral that acts directly against HPV (and does not rely on the host immune system) would be an important weapon against HPV infections and cancers, particularly in HIV/AIDS patients. Recent successes of small molecule inhibitors that interfere with the herpesvirus primase-helicase interaction justify using such an approach against HPV. Our collaborator (Melendy, UB) has identified an interaction between the HPV DNA replication helicase, E1, and human Topoisomerase I that appears to be vital for HPV genome duplication. They will evaluate a panel of E1 mutations predicted to disrupt the interaction with Topoisomerase to more fully define this interaction. We will analyze the structure of this interaction by SAXS ( in collaboration with the Snell Lab) and single crystal complexes of the two proteins. These data will provide information that will be useful in developing second generation inhibitors that could act as potential HPV antiviral therapeutics.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 人乳头瘤病毒（HPV）是最常见的性传播感染，几乎是所有宫颈和肛门生殖器，以及超过一半的口服癌症的原因。当前的HPV治疗是通过切除病变或免疫干预（作为免疫刺激剂或HPV疫苗以防止最常见的HPV感染）。尽管已经针对多种类型的病毒开发了抗病毒剂，但迄今为止，没有针对HPV的真正抗病毒药。由于对HPV治疗/预防的免疫系统的严重依赖，即使在HAART治疗后，HPV感染和癌症仍然是HIV/AIDS患者的主要问题。直接针对HPV作用的真正的HPV抗病毒（并且不依赖宿主免疫系统）将是针对HPV感染和癌症的重要武器，尤其是在HIV/AIDS患者中。小分子抑制剂的最新成功，这些抑制剂干扰了疱疹病毒原病毒酶 - 羟蛋白酶相互作用，可以使用这种方法对HPV进行合理。 我们的合作者（UB Melendy，UB）已经确定了HPV DNA复制解旋酶，E1和人拓扑异构酶I之间的相互作用，这对于HPV基因组重复似乎至关重要。他们将评估一个预计将破坏与拓扑异构酶相互作用的E1突变面板，以更全面地定义这种相互作用。我们将通过SAXS（与Snell Lab合作）和两种蛋白质的单晶复合物分析这种相互作用的结构。这些数据将提供对开发第二代抑制剂有用的信息，这些抑制剂可能充当潜在的HPV抗病毒疗法。