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Single and multi-component biguanide-based microbicides

单组分和多组分双胍类杀菌剂

基本信息

批准号：
7492524
负责人：
MOHAMED E LABIB
金额：
$ 14.81万
依托单位：
NOVAFLUX BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7492524
关键词：
Animal Model Antiviral Agents Arts Biguanides Binding Biochemical Biological Biological Assay Biological Models CCR5 gene CXCR4 Receptors Cervical Class Classification Clinical Clinical Trials Communication Compatible Coupled Daily Data Databases Development Drug Combinations Drug Formulations Drug Kinetics Evaluation Feedback Goals HIV-1 Immune response In Vitro Infection Inorganic Sulfates Intellectual Property Lead Local Microbicides Maintenance Medicine Molecular Mus Mutate Nature Online Systems Pharmaceutical Preparations Polyethylene Polyethylenes Positioning Attribute Preparation Production Progress Reports Property Protocols documentation Publications Relative (related person)Research Research Personnel Research Project Grants Scheme Site Staging Structure System Testing Therapeutic Index Time Toxic effect Treatment Protocols U-Series Cooperative Agreements Unspecified or Sulfate Ion Sulfates Vagina Vaginal Gel Virus Virus Replication Viscosity Work base college commercialization computerized data processing design drug discovery experimental analysis human subject human tissue in vivo in vivo Model inhibitor/antagonist member microbicide molecular modeling pre-clinical pressure programs scaffold sound transmission process

项目摘要

DESCRIPTION (provided by applicant): The quasi species nature of a human immunodeficiency virus type 1 (HIV-1) infection coupled with the virus's ability to rapidly mutate away from selective drug pressure has led to the use of multiple drugs in combination as the accepted paradigm for treating systemic HIV-1 infections. Therefore it is quite likely that to obtain a safe and effective anti-HIV-1 microbicide a similar approach will be employed. The long-term objectives this "Integrated preclinical program for topical microbicides", is to provide data that will help justify the clinical development and commercialization of polyethylene-hexamethylene biguanide (PEHMB or PEHMB-derived product) alone or as part of a combination regimen. PEHMB is a potent inhibitor of HIV-1 with minimal toxicity yielding a therapeutic index >1400. Mechanism of action studies has provided evidence that PEHMB's antiviral activity is due to interference with virus binding to the cellular receptors CXCR4 and CCR5. In addition, large-scale production of PEHMB is estimated to be extremely inexpensive (dollars/kg), and we have found PEHMB to be extremely compatible with and stable in normal vaginal gel viscosity building agents. All of these attributes are promising enough to warrant further preclinical evaluation of this compound. In preliminary studies we have also combined PEHMB with members of other classes of putative anti-HIV-1 microbicides including a sulfated dendrimer developed by Dr. Shengrund at Penn State College of Medicine. We propose in this Program to identify the best PEHMB-based combination of drug candidates to maximize the suppressive effect on HIV-1 transmission. This program will involve three research projects integrated into one program. Project I will continue to refine antiviral efficacy and cellular toxicity parameters of the PEHMB scaffold based on computational approaches coupled to iterative rounds of feedback from our biochemical and biological assay systems. In addition, in Project I we will purify PEHMB, work to understand its structure, perform pharmacokinetic and murine toxicity studies as well as begin pre-formulation and formulation work for use in in vivo experimentation and manufacturing schemes. Project II will have the important task of assessing the relative toxicity of PEHMB utilizing both in vitro and in vivo model systems while at the same time provide the intellectual lead in our understanding of the molecular mechanism(s) b y which the PBG class of compounds inhibit virus replication and elicit cellular toxicity. Project II will also examine the impact of microbicides on the intra-vaginal and cervical immune response utilizing well-defined animal models. In Project Ill, we will use state of the art in vitro and in vivo model systems to profile the antiviral efficacy of our lead compound or combination. Project III will examine preformulation parameters, and test the efficacy of the formulated products in vitro including systematic studies to develop combination microbicides based on PEHMB and then test these formulated combinations using xenograph model systems developed by the investigators. All of the efforts outlined in the three projects are focused on providing information needed to move PEHMB and its viable combinations from a pre-clinical to a clinical stage in the drug discovery/development pipeline, with the goal of offering a new class of compounds with specific mode of action distinct from other compounds currently in clinical trials.

描述（由申请人提供）：人类免疫缺陷病毒 1 型 (HIV-1) 感染的准物种性质，加上该病毒能够在选择性药物压力下快速突变的能力，导致联合使用多种药物作为治疗全身性 HIV-1 感染的公认范例。因此，为了获得安全有效的抗HIV-1杀微生物剂，很可能会采用类似的方法。该“局部杀菌剂临床前综合计划”的长期目标是提供数据，帮助证明聚乙烯-六亚甲基双胍（PEHMB 或 PEHMB 衍生产品）单独或作为联合方案的一部分的临床开发和商业化的合理性。 PEHMB 是一种有效的 HIV-1 抑制剂，毒性极小，治疗指数 >1400。作用机制研究提供的证据表明，PEHMB 的抗病毒活性是由于干扰病毒与细胞受体 CXCR4 和 CCR5 的结合。此外，PEHMB 的大规模生产估计极其便宜（美元/千克），而且我们发现 PEHMB 与普通阴道凝胶增粘剂极其相容且稳定。所有这些属性都足以保证对该化合物进行进一步的临床前评估。在初步研究中，我们还将 PEHMB 与其他类别的假定抗 HIV-1 杀菌剂的成员结合起来，包括宾夕法尼亚州立大学医学院的 Shengrund 博士开发的硫酸化树枝状聚合物。我们在此计划中建议确定基于 PEHMB 的最佳候选药物组合，以最大限度地发挥对 HIV-1 传播的抑制作用。该计划将把三个研究项目整合为一个计划。项目 I 将基于计算方法以及来自我们的生化和生物测定系统的迭代反馈，继续完善 PEHMB 支架的抗病毒功效和细胞毒性参数。此外，在项目一中，我们将纯化PEHMB，努力了解其结构，进行药代动力学和小鼠毒性研究，并开始用于体内实验和制造方案的预配制和配制工作。项目 II 的重要任务是利用体外和体内模型系统评估 PEHMB 的相对毒性，同时为我们理解 PBG 类化合物抑制病毒复制和引起细胞毒性的分子机制提供智力指导。项目 II 还将利用明确的动物模型研究杀菌剂对阴道内和宫颈免疫反应的影响。在项目III中，我们将使用最先进的体外和体内模型系统来分析我们的先导化合物或组合的抗病毒功效。项目III将检查预配制参数，并在体外测试配制产品的功效，包括系统研究开发基于PEHMB的组合杀菌剂，然后使用研究人员开发的异种模型系统测试这些配制的组合。这三个项目中概述的所有努力都集中于提供将 PEHMB 及其可行组合从药物发现/开发管道中的临床前阶段转移到临床阶段所需的信息，目标是提供一类具有不同于目前临床试验中的其他化合物的特定作用模式的新型化合物。