Antiviral Compounds that Target HPV18 DNA

靶向 HPV18 DNA 的抗病毒化合物

• 批准号: 7405383
• 负责人: CHRISTOPHER FISHER
• 金额: $ 49.84万
• 依托单位: NANOVIR, LLC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405383
• 关键词: Animal Model; Antiviral Agents; Binding Sites; Biological; Biological Assay; Biological Availability; Biological Response Modifiers; Cancer Etiology; Cells; Chemicals; Chemistry; Class; Clear Cell; Clinical; Clinical Trials; Complex; Condition; Cultured Cells; DNA; DNA Binding Agent; DNA Minor Groove Binding; DNA Sequence; Data; Development; Disease; Dissociation; Dose; Drug Formulations; Drug Industry; Elements; Episome; Exhibits; Freezing; Future; Genotype; Guanosine; Human; Human Papillomavirus; Human papilloma virus 31; Human papillomavirus 16; Human papillomavirus 18; Hydrogen Bonding; Imidazole; Immune system; In Vitro; Investigational Drugs; Libraries; Life Cycle Stages; Maintenance; Malignant neoplasm of cervix uteri; Measures; Methods; Minor Groove; Modeling; Numbers; Nylons; Operative Surgical Procedures; Papillomavirus; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Polymerase Chain Reaction; Pyrroles; Range; Replication Origin; Research; Risk; Safety; Series; Small Business Technology Transfer Research; Solid; Solutions; Southern Blotting; Specificity; Structure-Activity Relationship; Support System; Testing; Time; Topical agent; Toxic effect; Toxicology; United States Food and Drug Administration; Vaccines; Viral; Virus; Woman; Work; base; chemical property; chemical synthesis; design; dosage; drug development; improved; in vivo; indexing; keratinocyte; malignant breast neoplasm; monolayer; nano; pre-clinical; tool; uptake; viral DNA; Animal Model; Antiviral Agents; Binding Sites; Biological; Biological Assay; Biological Availability; Biological Response Modifiers; Cancer Etiology; Cells; Chemicals; Chemistry; Class; Clear Cell; Clinical; Clinical Trials; Complex; Condition; Cultured Cells; DNA; DNA Binding Agent; DNA Minor Groove Binding; DNA Sequence; Data; Development; Disease; Dissociation; Dose; Drug Formulations; Drug Industry; Elements; Episome; Exhibits; Freezing; Future; Genotype; Guanosine; Human; Human Papillomavirus; Human papilloma virus 31; Human papillomavirus 16; Human papillomavirus 18; Hydrogen Bonding; Imidazole; Immune system; In Vitro; Investigational Drugs; Libraries; Life Cycle Stages; Maintenance; Malignant neoplasm of cervix uteri; Measures; Methods; Minor Groove; Modeling; Numbers; Nylons; Operative Surgical Procedures; Papillomavirus; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Polymerase Chain Reaction; Pyrroles; Range; Replication Origin; Research; Risk; Safety; Series; Small Business Technology Transfer Research; Solid; Solutions; Southern Blotting; Specificity; Structure-Activity Relationship; Support System; Testing; Time; Topical agent; Toxic effect; Toxicology; United States Food and Drug Administration; Vaccines; Viral; Virus; Woman; Work; base; chemical property; chemical synthesis; design; dosage; drug development; improved; in vivo; indexing; keratinocyte; malignant breast neoplasm; monolayer; nano; pre-clinical; tool; uptake; viral DNA

DESCRIPTION (provided by applicant): This project will identify imidazole-pyrrole polyamides to be used as topical antiviral agents for the treatment of human papillomavirus (HPV). Current treatments, which include surgery, freezing, noxious agents, and "biological response modifiers" are primitive or non-specific. We hypothesize that several compounds with antiviral activity will be found among a library of imidazole-pyrrole polyamides targeting the HPV18 E1 binding site similar to our preliminary studies with HPV16 and HPV31. This Phase 1 study will establish a keratinocyte culture system that supports HPV18 episomal maintenance. Polyamides will be synthesized that target the HPV18 origin of replication (ori), and tested for their ability to suppress episomal DNA levels. Active compounds will then be tested in assays designed to confirm specificity and to establish baseline selectivity indices. To meet these objectives, the following specific aims will be pursued: Aim 1: Chemistry. The viral origin of replication (ori) for HPV18 will be targeted by synthesis of a series of polyamides designed to recognize the specific sequence of the HPV18 E1 binding site. Aim 2: The effects of polyamides on HPV18 replication and maintenance will be tested in cell culture. Aim 3: Compounds that produce a decrease in HPV18 DNA levels will be further characterized, conditions will be established for maximum antiviral effects in cell culture, and initial in vitro toxicity assessments will be conducted. Successful completion of these studies offers the promise of specific antiviral treatments for HPV. It is anticipated that compounds reducing viral DNA load will by themselves, or in conjunction with the host immune system in vivo, be ultimately sufficient to clear cells infected with HPV. These studies are important because they provide an alternative to the vaccine approaches to HPV which have come to dominate the pharmaceutical industry, while offering no hope to those people currently or soon to be infected with the virus. In addition, these studies may identify valuable research tools for use in understanding important aspects of the HPV life cycle. Future Phase 2 studies will test the efficacy of active compounds in complex cell culture models (raft cultures) and animal models of HPV-related disease. In addition, bioavailability studies will focus on developing optimal topical treatment formulations and upon measuring systemic exposure following topical treatments. These studies will be required to guide toxicological studies prior to testing in humans. Ultimately, the project seeks to use polyamides targeting one of the most prevalent cancer causing viruses (HPV18) as topical agents in a clinical setting. Human papillomavirus is the leading cause of cervical cancer, which is second only to breast cancer as a killer of women. There are currently no specific antiviral treatments for HPV. The studies described here are designed to identify agents that will be used as topical antiviral treatment s for HPV 18, one of the most important cancer-causing viruses.

描述（由申请人提供）：该项目将识别咪唑 - 吡咯的聚酰胺，用于治疗人乳头瘤病毒（HPV）的局部抗病毒剂。当前的治疗方法包括手术，冻结，有害剂和“生物反应修饰剂”是原始的或非特异性的。我们假设在靶向HPV18 E1结合位点的咪唑 - 吡咯聚酰胺聚酰胺库中发现了几种具有抗病毒活性的化合物，类似于我们对HPV16和HPV31的初步研究。这项第一阶段研究将建立一个支持HPV18偶发性维持的角质形成细胞培养系统。将合成靶向HPV18复制（ORI）的多酰胺，并测试其抑制偶发DNA水平的能力。然后，将在旨在确认特异性并建立基线选择性指数的测定中测试活性化合物。为了实现这些目标，将追求以下具体目标：目标1：化学。 HPV18复制的病毒起源（ORI）将通过合成一系列旨在识别HPV18 E1结合位点的特定序列的聚酰胺的靶向。 AIM 2：聚酰胺对HPV18复制和维持的影响将在细胞培养中进行测试。 AIM 3：将进一步表征HPV18 DNA水平降低的化合物，将建立条件以在细胞培养中的最大抗病毒作用，并将进行初始的体外毒性评估。这些研究的成功完成为HPV提供了特定的抗病毒治疗的希望。可以预期，减少病毒DNA负荷的化合物本身会或与体内的宿主免疫系统结合使用，最终足以清除感染HPV的细胞。这些研究之所以重要，是因为它们为HPV的疫苗方法提供了替代方案，这些方法已经主导了制药行业，同时对目前或很快被病毒感染的那些人没有希望。此外，这些研究可能会确定有价值的研究工具，以理解HPV生命周期的重要方面。未来的2阶段研究将测试活性化合物在复杂细胞培养模型（筏培养物）和与HPV相关疾病的动物模型中的疗效。此外，生物利用度研究将着重于开发最佳的局部治疗制剂，并在局部治疗后测量全身性暴露后。这些研究将需要在人类测试之前指导毒理学研究。最终，该项目试图使用针对临床环境中最普遍的引起病毒（HPV18）的癌症之一（HPV18）的聚酰胺。 人乳头瘤病毒是宫颈癌的主要原因，宫颈癌仅次于乳腺癌作为女性的杀手。目前尚无针对HPV的特定抗病毒治疗。此处描述的研究旨在确定将用作HPV 18的局部抗病毒治疗的药物，这是最重要的致癌病毒之一。