Synthesis of Novel Water-Soluble Glycodendrimers as Anti-HIV Agents

作为抗 HIV 药物的新型水溶性糖聚合物的合成

• 批准号: 7848773
• 负责人: KATHERINE D MCREYNOLDS
• 金额: $ 1.77万
• 依托单位: CALIFORNIA STATE UNIVERSITY SACRAMENTO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848773
• 关键词: Acids; Acquired Immunodeficiency Syndrome; Advanced Development; Adverse effects; Affinity; Alcohols; Amination; Amines; Anti-HIV Agents; Antiviral Agents; Architecture; Binding; Biological Assay; Carbohydrates; Cell Communication; Cell Line; Cell surface; Cells; Complex; Coupled; Coupling; Dendrimers; Development; Effectiveness; Electrostatics; Fuzeon; Generations; Goals; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV Infections; HIV Seropositivity; Highly Active Antiretroviral Therapy; Human; Individual; Infection; Inorganic Sulfates; Lead; Length; Libraries; Longevity; Longitudinal Studies; Membrane Proteins; Methodology; Mind; N-terminal; Nature; Patients; Pharmaceutical Preparations; Positioning Attribute; Principal Investigator; Process; Property; Protease Inhibitor; Proteins; Quality of life; RNA-Directed DNA Polymerase; Reporting; Research; Research Proposals; Resistance; Resistance development; Series; Shapes; Structure; Surface; Testing; Therapeutic; Toxic effect; Training; Unspecified or Sulfate Ion Sulfates; Upper arm; Vaccines; Viral; Virulent; Virus; Water; base; experience; graduate student; improved; inhibitor/antagonist; novel; particle; prevent; programs; receptor; sound; sugar; sulfated polymer; sulfation; three dimensional structure; viral resistance

DESCRIPTION (provided by applicant): The goal of the proposed research entails the synthesis of glycodendrimers capable of binding to the HIV surface protein gp120, and blocking subsequent interactions with the host cell leading up to viral entry. Gp120 is present on the surface of HIV complexed with membrane protein gp41 as a heterotrimer. The gp120/gp41 complex, upon binding to cell surface CD4, undergoes a conformational change, exposing the N-terminal region of gp41. Gp120 next binds cell surface co-receptors via electrostatic interactions, that strengthen the virus-host cell interactions, allowing for subsequent gp41 fusion, pore formation, and ultimately, viral entry. It has been reported that the viral fusion/entry process is cooperative, requiring multiple copies of CD4, host cell co-receptors, and clustering of the gp41/gp120 heterotrimer. Due to the multivalent nature of the viral fusion/entry process, it is hypothesized that the glycodendrimers will be capable of binding to multiple copies of gp120 simultaneously, preventing viral entry. The shape, number of carbohydrates, and size of the glycodendrimers are expected to be the significant contributing factors determining the anti-HIV activity. The hypothesis will be tested through accomplishment of four specific aims. SA#1 describes the synthesis of interchangeable dendrimer linkers and differentially branched cores. SA#2 outlines the synthesis of discrete carbohydrate-linker conjugates, primed for coupling to the branched dendrimer cores. SA#3 depicts the construction of a variety of branched glycodendrimers to evaluate the specific architectural features necessary for optimum binding to gp120, and inhibition of viral infectivity, which will be evaluated in the fourth specific aim (SA#4). Preliminary research indicates that the synthetic methodologies are sound and that the target glycodendrimers can be synthesized and evaluated for their anti-HIV properties within the timeframe of the project. The proposed research seeks to fill a void in the anti- HIV drug arsenal by providing lead compounds specifically targeting viral gp120. Relevance: In the U.S., there are 850,000-950,000 HIV-infected people, with an additional 180,000-280,000 unaware they are HIV-positive. Due to adverse side-effects and decreased drug effectiveness caused by viral resistance, the development of new anti-HIV drugs is crucial in maintaining longevity and quality of life for infected individuals. This research seeks to develop a new class of anti-HIV drugs.

描述（由申请人提供）：拟议研究的目标需要合成能够结合HIV表面蛋白gp120的糖树状聚合物，并阻断随后与宿主细胞的相互作用，导致病毒进入。Gp120以异源三聚体形式与膜蛋白gp41复合物存在于HIV表面。gp120/gp41复合物与细胞表面CD4结合后，发生构象变化，暴露gp41的n端区域。Gp120随后通过静电相互作用结合细胞表面共受体，加强病毒宿主细胞相互作用，允许gp41随后融合、形成孔，并最终使病毒进入。据报道，病毒融合/进入过程是合作的，需要CD4、宿主细胞共受体的多个拷贝，以及gp41/gp120异源三聚体的聚集。由于病毒融合/进入过程的多价性质，假设糖树状聚合物能够同时结合gp120的多个拷贝，从而阻止病毒进入。糖树状大分子的形状、碳水化合物的数量和大小被认为是决定抗hiv活性的重要因素。该假设将通过实现四个具体目标来检验。SA#1描述了可互换的树突连接体和差异分支核的合成。SA#2概述了离散碳水化合物-连接物偶联物的合成，用于偶联到分支树状大分子核心。SA#3描述了各种支链糖树状聚合物的构建，以评估与gp120最佳结合所需的特定结构特征，并抑制病毒感染，这将在第四个特定目标（SA#4）中进行评估。初步研究表明，合成方法是合理的，目标糖树状大分子可以在项目的时间框架内合成和评估其抗hiv特性。提出的研究旨在通过提供特异性靶向病毒gp120的先导化合物来填补抗HIV药物库中的空白。相关性：在美国，有85万至95万艾滋病毒感染者，另有18万至28万不知道自己是艾滋病毒阳性。由于病毒耐药性引起的不良副作用和药物有效性下降，开发新的抗艾滋病毒药物对于维持感染者的寿命和生活质量至关重要。这项研究旨在开发一类新的抗艾滋病药物。