Antiviral Compounds for Human Papillomavirus 16

针对人乳头瘤病毒 16 的抗病毒化合物

基本信息

批准号：
6908154
负责人：
CHRISTOPHER FISHER
金额：
$ 38.85万
依托单位：
NANOVIR, LLC.
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2007-06-30
项目状态：
已结题

项目摘要

This project seeks imidazole-pyrrole polyamides to be used as topical antiviral agents for the treatment of human papillomavirus (HPV). HPV, especially in its sexually-transmitted forms, presents a major public health problem throughout the world. Current treatments, which include surgery, freezing, noxious agents, and =biological response modifiers," are primitive or non-specific. One reason for the lack of treatment alternatives is the small size of the viral genome, and the corresponding lack of antivirai targets. For this reason, the alternative approach of targeting HPV DNA using sequence-specific DNA binding agents is being taken. The HPV origin of replication (on) contains binding sites for the viral-encoded replication proteins E1 and E2, which are required for viral replication and maintenance. Targeting the or/with sequence-specific DNA binding agents has the potential to block the action of E1 and E2, thereby disrupting processes required for maintenance in cells. Preliminary work with HPV31 has shown significant promise, lmidazole-pyrrole polyamides, designed to target the HPV31 E1 binding site, were found to potently reduce HPV31 episomal DNA levels in cells. We now request supped for the design, synthesis, and testing of compounds that target the commercially important HPV16 genotype. Similar to our preliminary studies with HPV31, we hypothesize that several compounds with antiviral activity will be found among a library of imidazole-pyrrole polyamides targeting the HPV16 E1 binding site. This Phase I study will establish a keratinocyte culture system that supports HPV16 episomal maintenance. Polyamides will be synthesized that target the HPV16 origin of replication (on), and tested for their ability to suppress episomal DNA levels. To meet these objectives, the following specific aims were identified: Aim 1: The viral origin or replication (ori) will be targeted via synthesis of a series of polyamides recognizing the specific sequence of the canonical E1 binding site associated with HPV16. Aim 2: The effects of polyamides on HPV16 replication and maintenance will be tested in cell culture. Aim 3: Positive results showing a decrease in HPV16 DNA levels will be further characterized, and conditions will be established for maximum antiviral effects in cell culture. Successful completion of these studies offers the promise of successful antiviral treatments for HPV. These studies are important because they provide an alternative to the vaccine approaches to HPV therapy. Such approaches have come to dominate the pharmaceutical industry, while offedng no hope to those people currently infected with the virus. In addition, these studies may identifyvaluable research tools for use in understanding important aspects of the HPV life cycle. Phase II 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 the most prevalent cancer causing virus (HPV16) as topical agents in a clinical setting.

该项目寻求咪唑 - 吡咯聚酰胺作为治疗人乳头瘤病毒（HPV）的局部抗病毒剂。 HPV，尤其是其性传播形式，在世界范围内提出了一个主要的公共卫生问题。当前的治疗方法包括手术，冻结，有害的药物和=生物反应修饰剂，“是原始的或非特异性的。缺乏治疗替代方法的原因之一是病毒基因组的尺寸很小，并且缺乏抗毒素靶标的。出于此原因，使用序列HPV DNA使用序列DNA的替代方法是使用序列DNA的替代方法。复制的HPV起源（ON）包含病毒编码复制蛋白E1和E2的结合位点，这是病毒复制和维持所需的。用序列特异性DNA结合剂靶向OR//有可能阻止E1和E2的作用，从而破坏细胞中维持所需的过程。 HPV31的初步工作显示出巨大的希望，Lmidazole-Pyrrole聚酰胺，旨在针对HPV31 E1结合位点，发现可有效降低细胞中的HPV31偶发性DNA水平。现在，我们要求对针对商业重要HPV16基因型的化合物的设计，合成和测试。与我们对HPV31的初步研究类似，我们假设在靶向HPV16 E1结合位点的咪唑 - 吡咯聚酰胺库中将发现几种具有抗病毒活性的化合物。这项I阶段研究将建立一个支持HPV16偶发性维持的角质形成细胞培养系统。聚酰胺将合成，以靶向 HPV16复制的起源（ON），并测试了它们抑制偶发DNA水平的能力。为了实现这些目标，确定了以下具体目标： AIM 1：通过合成一系列聚酰胺，识别与HPV16相关的规范E1结合位点的特定序列的一系列聚酰胺序列，将针对病毒起源或复制（ORI）。 AIM 2：聚酰胺对HPV16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HPV16 DNA水平降低的阳性结果，并将建立条件以在细胞培养中的最大抗病毒作用。这些研究的成功完成为HPV成功提供了抗病毒治疗的希望。这些研究很重要，因为它们为HPV治疗的疫苗方法提供了替代方法。这种方法已经统治了制药行业，而那些目前感染该病毒的人没有希望。此外，这些研究可以识别可用于理解HPV生命周期重要方面的可使用研究工具。第二阶段的研究将测试活性化合物在复杂细胞培养模型（RAFT培养物）和与HPV相关疾病的动物模型中的功效。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。这些研究将需要指导毒理学研究在人类进行测试之前。最终，该项目试图使用靶向最普遍的导致病毒（HPV16）作为局部环境中的局部药物的聚酰胺。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Improved Antiviral Activity of a Polyamide Against High-Risk Human Papillomavirus Via N-Terminal Guanidinium Substitution.

DOI：
10.1039/c6md00371k
发表时间：
2016-11-01
期刊：
MedChemComm
影响因子：
0
作者：
Castaneda CH;Scuderi MJ;Edwards TG;Harris GD Jr;Dupureur CM;Koeller KJ;Fisher C;Bashkin JK
通讯作者：
Bashkin JK

DNA damage repair genes controlling human papillomavirus (HPV) episome levels under conditions of stability and extreme instability.

DOI：
10.1371/journal.pone.0075406
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Edwards TG;Vidmar TJ;Koeller K;Bashkin JK;Fisher C
通讯作者：
Fisher C

DNA Binding Polyamides and the Importance of DNA Recognition in their use as Gene-Specific and Antiviral Agents.

DNA 结合聚酰胺以及 DNA 识别在其用作基因特异性药物和抗病毒药物中的重要性。

DOI：
10.4172/2161-0444.1000162
发表时间：
2014
期刊：
Medicinal chemistry
影响因子：
2.3
作者：
Koeller,KevinJ;Harris,GDavis;Aston,Karl;He,Gaofei;Castaneda,CarlosH;Thornton,MelissaA;Edwards,TerriG;Wang,Shuo;Nanjunda,Rupesh;Wilson,WDavid;Fisher,Chris;Bashkin,JamesK
通讯作者：
Bashkin,JamesK

Recent Insights into the Control of Human Papillomavirus (HPV) Genome Stability, Loss, and Degradation.