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

基本信息

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
项目类别：
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

项目摘要

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）：拟议研究的目的是需要合成能够与HIV表面蛋白GP120结合的糖结二聚体，并阻止随后与导致病毒进入的宿主细胞的相互作用。 GP120存在于与膜蛋白GP41复合物作为异三聚体的HIV表面上。 GP120/GP41复合物与细胞表面CD4结合后，经历了构象变化，暴露了GP41的N末端区域。 GP120接下来通过静电相互作用结合细胞表面共受体，从而增强了病毒宿主的细胞相互作用，从而允许随后的GP41融合，孔形成，并最终导致病毒进入。据报道，病毒融合/进入过程是合作的，需要多个CD4的副本，宿主细胞共受体和GP41/GP120异晶合体的聚类。由于病毒融合/进入过程的多价性质，因此假设糖胶合体将能够同时与多个GP120的副本结合，从而防止病毒进入。预期糖结基因元素的形状，碳水化合物的数量和大小是决定抗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描述了可互换的树枝状聚合物接头和差异分支的核心的合成。 SA＃2概述了离散的碳水化合物链链缀合物的合成，用于与分支树枝状聚合物核耦合。 SA＃3描述了各种分支糖胶质聚体的构建，以评估最佳结合与GP120所需的特定结构特征，并抑制病毒感染性，这将在第四个特定目标中进行评估（SA＃4）。初步研究表明，合成方法是合理的，并且可以在项目时间范围内合成和评估其抗HIV特性。拟议的研究试图通过提供专门针对病毒GP120的铅化合物来填补抗HIV药物库中的空隙。相关性：在美国，有850,000-950,000人感染了HIV的人，额外的180,000-280,000不知道他们是HIV阳性的。由于副作用不良和因病毒抗性引起的药物有效性的降低，新的抗HIV药物的发展对于维持感染者的寿命和生活质量至关重要。这项研究旨在开发新的抗HIV药物。