Engineering Nanoscale Aptamer-based Biomaterials that Target Cellular Receptors

针对细胞受体的工程纳米适体生物材料

• 批准号: 8345177
• 负责人: Ravi S. Kane
• 金额: $ 33.43万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-06 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8345177
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Address; Adverse effects; Anti-Retroviral Agents; Avidity; Binding; Biocompatible Materials; Biological; Biomimetics; Bone Marrow; CCR5 gene; Cells; Chemokine (C-C Motif) Receptor 5; Drug Formulations; Engineering; Evolution; Extracellular Domain; HIV; HIV Infections; HIV vaccine; HIV-1; Individual; Infection; Infection prevention; Intervention; Ligands; Liver; Mediating; Methods; Modeling; Mutation; Nature; Oligonucleotides; Persons; Pharmaceutical Preparations; Public Health; Regimen; Research; Resistance; Safety; System; Thymus Gland; Vaccines; Viral; Virus; Work; aptamer; base; biomaterial compatibility; cellular targeting; chemokine receptor; controlled release; cost; cost effective; design; improved; in vivo; inhibitor/antagonist; innovation; interest; microbicide; model design; mouse model; nanoscale; novel; pandemic disease; pathogen; prevent; programs; receptor; resistant strain; scaffold; single molecule; targeted delivery; transmission process; viral resistance

DESCRIPTION (provided by applicant): The objective of the proposed work is to develop and characterize potent aptamer-based biomaterials that recognize host cellular receptors based on a biomimetic strategy - polyvalency. Nature makes use of polyvalent interactions, involving the simultaneous binding of multiple ligands on one biological entity to multiple receptors on another, to strengthen the avidity of interactions significantly. The proposed studies will use polyvalency to develop and characterize potent heterodivalent and polyvalent microbicides that bind to CCR5 receptors and prevent infection by a model pathogen, HIV. Although the use of cocktails of antiretroviral drugs has had a major impact on the treatment of AIDS in the developed world, there are problems associated with these regimens including serious side effects, high costs, and the emergence of resistant strains. In the context of the global pandemic, there remains a critical need for strategies to prevent the transmission of the virus. Given the lack of an effective HIV vaccine, an effective microbicidal formulation applied prior to intercourse to block the virus before infection is established remains our best hope to arrest this terrible pandemic in the short term. Moreover, the active components of such formulations must be potent, cost effective, and address the problem of emergence of viral resistance. The first aim of the proposed work is to identify short oligonucleotide aptamers that bind to different domains of CCR5. The second aim is to optimize the biocompatibility and activity of aptamer-based heterodivalent and polyvalent inhibitors. The third aim is to characterize inhibitory efficac in vivo using a new humanized bone marrow/liver/thymus (huBLT) mouse model and to design formulations for the controlled release of the heterodivalent and polyvalent inhibitors over an extended period to improve microbicide acceptability. We anticipate that these novel heterodivalent and polyvalent inhibitors will effectively block CCR5-mediated entry of HIV into target cells. Active heterodivalent and polyvalent CCR5-targeted inhibitors should help address the important problem of resistance to HIV inhibitors because: CCR5 is a static target, not prone to the high mutation rate of HIV-1; persons with a genetic defect in CCR5 expression are highly resistant to infection with HIV-1, but are otherwise normal, healthy individuals; and most cases of HIV-1 transmission involve viral strains that use CCR5 for entry, and such strains predominate during the establishment of infection. The use of short aptamers will make the approach practical from a cost perspective. The proposed heterodivalent and polyvalent microbicides represent innovative new formulations that combine multiple interventions (ligands targeted towards different extracellular domains of CCR5) within a single molecule. We anticipate that our proposed research program will result in novel HIV microbicides with improved efficacy, safety, and acceptability, providing a powerful means to prevent the transmission of this globally-important pathogen. PUBLIC HEALTH RELEVANCE: The proposed work will focus on the engineering of nanoscale aptamer-based biomaterials for the potent and specific recognition of cellular receptors. These studies will contribute to a fundamental understanding of polyvalent biorecognition, which is important for the design of inhibitors and targeted delivery systems. The research is also relevant to public health because the design of heterodivalent and polyvalent receptor-directed molecules represents a powerful approach for preventing the transmission of pathogens and limiting the emergence of resistant strains.

描述（由申请人提供）：拟议工作的目的是开发和表征基于适体的有效的生物材料，这些生物材料识别基于仿生策略的宿主细胞受体 - 多价。大自然可以利用多价相互作用，涉及多种配体在一个生物实体上与另一个生物体上的多个受体的同时结合，以显着增强相互作用的亲和力。拟议的研究将使用多性价值来发展和表征与CCR5受体结合并防止模型病原体HIV感染的有效异差和多价杀菌剂。尽管使用抗逆转录病毒药物的鸡尾酒对发达国家的艾滋病治疗产生了重大影响，但与这些方案有关的问题，包括严重的副作用，高成本和抗性菌株的出现。在全球大流行的背景下，仍然需要迫切需要防止病毒传播的策略。鉴于缺乏有效的艾滋病毒疫苗，在建立感染之前在性交之前应用的有效的杀生型疫苗仍然是我们最大的希望 短期内糟糕的大流行。此外，这种制剂的主动组成部分必须有效，具有成本效益，并解决了病毒抗性的出现问题。拟议工作的第一个目的是确定与CCR5不同域结合的短寡核苷酸适体。第二个目的是优化基于适体的异差和多价抑制剂的生物相容性和活性。第三个目的是使用新的人源化骨髓/肝/胸腺（Hublt）小鼠模型来表征体内抑制性效果，并在长时间内设计出杂质和多价抑制剂的控制配方，以改善微生物可接受性。我们预计这些新型的异差和多价抑制剂将有效阻止CCR5介导的HIV进入靶细胞。主动异差和多价CCR5靶向抑制剂应有助于解决对HIV抑制剂抗性的重要问题，因为：CCR5是静态靶标，不容易发生HIV-1的高突变率； CCR5表达中遗传缺陷的人对HIV-1的感染具有高度抗性，但否则是正常的，健康的个体。 HIV-1传播的大多数病例都涉及使用CCR5进入的病毒菌株，在建立感染期间，这种菌株占主导地位。从成本的角度来看，使用简短的适应器将使方法实用。提出的异差和多价微生物代表了创新的新制剂，它们结合了单个分子中多种干预措施（针对CCR5的不同细胞外域的配体）。我们预计，我们提出的研究计划将导致新型的HIV杀菌剂，并提高疗效，安全性和可接受性，从而提供强大的手段来防止这种全球重要的病原体传播。 公共卫生相关性：拟议的工作将重点放在基于纳米级适体的生物材料的工程上，以实现对细胞受体的有效和特定识别。这些研究将有助于对多价生物识别的基本理解，这对于抑制剂和靶向递送系统的设计很重要。这项研究也与公共卫生有关，因为杂质和多价受体指导的分子的设计是防止病原体传播和限制抗性菌株的出现的强大方法。