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: 8711082
• 负责人: Ravi S. Kane
• 金额: $ 31.11万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711082
• 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.

描述（由申请人提供）：拟议工作的目的是开发和表征有效的基于适体的生物材料，该材料基于仿生策略（多价）识别宿主细胞受体。大自然利用多价相互作用，包括一个生物实体上的多个配体与另一个生物实体上的多个受体同时结合，显着增强相互作用的亲合力。拟议的研究将利用多价来开发和表征有效的异二价和多价杀菌剂，这些杀菌剂可与 CCR5 受体结合并预防模型病原体 HIV 的感染。尽管抗逆转录病毒药物混合物的使用对发达国家的艾滋病治疗产生了重大影响，但这些治疗方案也存在一些问题，包括严重的副作用、高成本和耐药菌株的出现。在全球大流行的背景下，仍然迫切需要制定防止病毒传播的策略。鉴于缺乏有效的艾滋病毒疫苗，在性交前应用有效的杀菌剂以在感染发生之前阻断病毒仍然是我们阻止这种情况的最大希望 短期内会发生可怕的大流行。此外，此类制剂的活性成分必须有效、具有成本效益，并解决病毒耐药性出现的问题。拟议工作的首要目标是鉴定与 CCR5 不同结构域结合的短寡核苷酸适体。第二个目标是优化基于适配体的异二价和多价抑制剂的生物相容性和活性。第三个目标是使用新的人源化骨髓/肝脏/胸腺（huBLT）小鼠模型来表征体内抑制功效，并设计用于在较长时间内控制释放异二价和多价抑制剂的制剂，以提高杀菌剂的可接受性。我们预计这些新型异二价和多价抑制剂将有效阻止 CCR5 介导的 HIV 进入靶细胞。活性异二价和多价 CCR5 靶向抑制剂应有助于解决 HIV 抑制剂耐药性的重要问题，因为： CCR5 是静态靶点，不易发生 HIV-1 的高突变率； CCR5 表达存在遗传缺陷的人对 HIV-1 感染具有高度抵抗力，但在其他方面是正常、健康的个体；大多数 HIV-1 传播病例​​涉及使用 CCR5 进入的病毒株，并且此类病毒株在感染建立期间占主导地位。从成本角度来看，短适体的使用将使该方法变得实用。所提出的异二价和多价杀菌剂代表了创新的新配方，在单个分子内结合了多种干预措施（针对 CCR5 不同细胞外结构域的配体）。我们预计，我们提出的研究计划将产生具有更高功效、安全性和可接受性的新型艾滋病毒杀微生物剂，为防止这种全球重要病原体的传播提供强有力的手段。