PATHOGENIC PROTEIN INTERACTIONS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 人乳头瘤病毒(HPV)是最常见的性传播感染，几乎所有的宫颈癌和肛门癌以及超过一半的口腔癌都是由它引起的。目前的HPV治疗方法是切除病变或通过免疫干预(咪喹莫特作为免疫刺激剂，或HPV疫苗以防止感染最常见的HPV)。虽然已经开发出针对许多类型病毒的抗病毒药物，但到目前为止还没有真正的抗病毒药物可用于治疗HPV。由于严重依赖免疫系统进行HPV治疗/预防，HPV感染和癌症仍然是艾滋病毒/艾滋病患者的主要问题，即使在HAART治疗之后也是如此。一种直接对抗HPV的真正的HPV抗病毒药物(不依赖于宿主免疫系统)将是对抗HPV感染和癌症的重要武器，特别是在艾滋病毒/艾滋病患者中。最近干扰疱疹病毒启动酶-解旋酶相互作用的小分子抑制剂的成功证明了使用这种方法来治疗HPV是合理的。我们的合作者(Melendy，UB)已经确定了HPV DNA复制解旋酶E1和人类拓扑异构酶I之间的相互作用，这似乎对HPV基因组复制至关重要。他们将评估一组预测会扰乱与拓扑异构酶相互作用的E1突变，以更全面地定义这种相互作用。我们将通过SAXS(与Snell实验室合作)和两种蛋白质的单晶复合体来分析这种相互作用的结构。这些数据将提供有用的信息，用于开发可能作为潜在的HPV抗病毒疗法的第二代抑制剂。

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.