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）感染的准物质性质，以及该病毒迅速从选择性药物压力迅速突变的能力，导致多种药物将多种药物组合为接受的范式，以治疗全身HIV-1感染。因此，很有可能要采用安全有效的抗HIV-1微生物，采用类似的方法。长期目标“局部杀微生物的综合临床前计划”是提供数据，有助于单独或单独使用聚乙烯 - 己二甲基Biguanide（PEHMB或PEHMB衍生产品）的临床开发和商业化合理性或作为合并方案的一部分。 PEHMB是一种有效的HIV-1抑制剂，具有最小的毒性，可提供治疗指数> 1400。作用研究机理提供了证据，表明PEHMB的抗病毒活性是由于干扰了与细胞受体CXCR4和CCR5结合的病毒。此外，PEHMB的大规模生产估计非常便宜（美元/千克），我们发现PEHMB与正常的阴道凝胶粘度建筑剂中的PEHMB非常兼容并稳定。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与其他类别的抗HIV-1杀菌剂的成员结合在一起，包括宾夕法尼亚州立医学院的Shengrund博士开发的硫化树枝状聚合物。我们建议在该计划中确定最佳的基于PEHMB的候选药物组合，以最大程度地提高对HIV-1传播的抑制作用。该计划将涉及将三个研究项目集成到一个计划中。项目我将继续根据我们的生物化学和生物学测定系统的迭代回合，基于与迭代的反馈相结合的计算方法，以完善PEHMB支架的抗病毒功效和细胞毒性参数。此外，在项目中，我们将净化PEHMB，以了解其结构，进行药代动力学和鼠毒性研究，并开始在体内实验和制造方案中使用预制定和配方工作。项目II的重要任务是评估PEHMB利用体外和体内模型系统的相对毒性，同时为我们理解PBG类化合物抑制病毒复制并引起细胞毒性的分子机制（S）B Y提供了智力领导。项目II还将检查使用明确定义的动物模型的微生物对阴道内和宫颈免疫反应的影响。在ILL项目中，我们将在体外和体内模型系统中使用最新技术来介绍铅化合物或组合的抗病毒功效。项目III将检查预制参数，并在体外测试配方产品的疗效，包括系统研究以基于PEHMB开发组合菌物，然后使用研究人员开发的Xenography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在提供PEHMB及其可行组合所需的信息，从临床前的临床阶段到药物发现/开发管道中的临床阶段，其目的是提供新的化合物，其具有与当前临床试验中其他化合物不同的特定作用方式。