Can mannosylated dendrimers inhibit HIV-1 infection of DC-SIGN expressing cells

甘露糖化树枝状聚合物能否抑制 DC-SIGN 表达细胞的 HIV-1 感染

• 批准号: 7230592
• 负责人: Cara-Lynne Schengrund
• 金额: $ 18.37万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230592
• 关键词: Abbreviations; Acquired Immunodeficiency Syndrome; Amines; Antibodies; Antibody Specificity; Antigen-Presenting Cells; Antigens; Bacteria; Binding; Blood Circulation; Body Surface; Bovine Serum Albumin; Buffers; Calcium Binding; Cell physiology; Cell surface; Cells; Complex; Cytomegalovirus; Dendrimers; Dendritic Cells; Dengue Virus; Dermal; Disadvantaged; Enzyme-Linked Immunosorbent Assay; Epitopes; Fluorescence Resonance Energy Transfer; Fluorescent Probes; Generations; Glare; Glycoproteins; Glycosphingolipids; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Hepatitis C virus; Immune response; Indirect Immunofluorescence; Infection; Intercellular Adhesion Molecules; Intercellular Junctions; Label; Lectin; Ligands; Localized; Location; Lymphoid Tissue; Lysosomes; MALDI-TOF Mass Spectrometry; Mannose; Mannose-Binding Lectins; Mass Spectrum Analysis; Mediating; Membrane; Membrane Microdomains; Methylphenazonium Methosulfate; Microscopy; Monitor; Mucous Membrane; Organelles; Pathway interactions; Performance; Pharmaceutical Preparations; Phosphate Buffer; Play; Polymers; Prevention approach; Process; Reagent; Research; Research Personnel; Risk; Role; Saline; Sodium Chloride; Solid; Surface; Surface Plasmon Resonance; T-Lymphocyte; Testing; Tetrazolium; Therapeutic; Thin Layer Chromatography; Tromethamine; Tweens; Uranium; Viral; Virion; Virus; Virus Diseases; base; cell type; chemokine; design; inhibitor/antagonist; pathogen; polypropyleneimine; programs; receptor; receptor function; research study; uptake

DESCRIPTION (provided by applicant): Dendritic cells (DCs) found in dermal and mucosal tissue express the lectin, DC-specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN), a mannose binding, calcium dependent, lectin. Because DCs are found at mucosal surfaces, they are one of the first cell types exposed to HIV-1 and their cell surface DC-SIGN binds it by adhering to mannose residues present on gp120. While binding and uptake mediated by DC-SIGN is considered to play an important role in the immune response, in some instances it facilitates viral infection. Its interaction with HIV-1 and 2 is an example of this. DC-SIGN has been found to bind other viruses including Ebola, hepatitis C virus, cytomegalovirus and Dengue virus, as well as different bacteria. In studies of infection of DC-SIGN expressing cells by Ebola, it was found that a hyperbranched dendritic polymer (dendrimer) derivatized with mannose residues was able to inhibit the receptor function of the DC lectin . Similar studies have not been carried out with HIV. This is a glaring deficit since mannose- specific lectins were found to inhibit infection of T lymphocytes by HIV-1, presumably by binding the mannose residues and blocking DC-SIGN binding to gp120. These observations provide a solid base for the hypothesis that mannosylated dendrimers might inhibit infection by HIV as well. Proposed experiments are designed to determine whether mannosylated dendrimers are effective ligands for DC-SIGN and if so whether they inhibit the interaction of DC-SIGN with gp120. Once an effective inhibitor is identified, experiments will be carried out to determine whether it is taken up by cells. If as anticipated, mannosylated dendrimers are effective inhibitors of the binding of rgp120 by DC-SIGN-expressing target cells, it will provide a new potential therapeutic approach for the prevention of HIV-1, and would support the hypothesis that multivalent mannosylated compounds might be effective at inhibiting the interaction of other pathogens that utilize the DC-SIGN pathway. It is these possibilities that make this research worth the risk.

描述（由申请人提供）：在真皮和粘膜组织中发现的树突状细胞（DC）表达凝集素，DC特异性细胞间粘附分子抓取非整联蛋白（DC-SIGN），一种甘露糖结合、钙依赖性凝集素。由于DC存在于粘膜表面，因此它们是暴露于HIV-1的第一种细胞类型之一，并且它们的细胞表面DC-SIGN通过粘附于gp 120上存在的甘露糖残基来结合HIV-1。虽然DC-SIGN介导的结合和摄取被认为在免疫应答中起重要作用，但在某些情况下，它促进病毒感染。它与HIV-1和2的相互作用就是一个例子。DC-SIGN已被发现结合其他病毒，包括埃博拉病毒，丙型肝炎病毒，巨细胞病毒和登革热病毒，以及不同的细菌。在埃博拉病毒感染DC-SIGN表达细胞的研究中，发现用甘露糖残基衍生的超支化树枝状聚合物（树枝状聚合物）能够抑制DC凝集素的受体功能。尚未对艾滋病毒进行类似的研究。这是一个明显的缺陷，因为发现甘露糖特异性凝集素抑制HIV-1对T淋巴细胞的感染，推测是通过结合甘露糖残基并阻断DC-SIGN与gp 120的结合。这些观察结果为甘露糖基化树状聚合物也可能抑制HIV感染的假设提供了坚实的基础。拟议的实验旨在确定甘露糖基化树枝状聚合物是否是DC-SIGN的有效配体，如果是，它们是否抑制DC-SIGN与gp 120的相互作用。一旦确定了有效的抑制剂，将进行实验以确定它是否被细胞吸收。如果如预期的那样，甘露糖基化树枝状聚合物是表达DC-SIGN的靶细胞与rgp 120结合的有效抑制剂，则它将为预防HIV-1提供新的潜在治疗方法，并将支持多价甘露糖基化化合物可能有效抑制利用DC-SIGN途径的其他病原体的相互作用的假设。正是这些可能性使这项研究值得冒险。