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

描述（由申请人提供）：拟议研究的目标是合成能够与HIV表面蛋白gp 120结合的糖树枝状聚合物，并阻断随后与宿主细胞的相互作用，导致病毒进入。Gp 120作为异源三聚体存在于与膜蛋白gp 41复合的HIV表面上。gp 120/gp 41复合物在与细胞表面CD 4结合后发生构象变化，暴露gp 41的N-末端区域。gp 120接下来通过静电相互作用结合细胞表面共受体，这加强了病毒-宿主细胞相互作用，允许随后的gp 41融合、孔形成和最终的病毒进入。据报道，病毒融合/进入过程是协同的，需要多个拷贝的CD 4、宿主细胞共受体和gp 41/gp 120异源三聚体的聚集。由于病毒融合/进入过程的多价性质，假设糖树枝状聚合物将能够同时结合gp 120的多个拷贝，防止病毒进入。糖树枝状聚合物的形状、碳水化合物的数量和大小预计是决定抗HIV活性的重要因素。将通过实现四个具体目标来检验这一假设。SA#1描述了可互换的树枝状聚合物接头和差异支化核的合成。SA#2概述了离散的碳水化合物-接头缀合物的合成，其被引发用于偶联至支链树枝状聚合物核心。SA#3描述了多种支链糖树枝状聚合物的构建，以评价与gp 120的最佳结合和病毒感染性抑制所需的特定结构特征，这将在第四个具体目标（SA#4）中进行评价。初步研究表明，合成方法是合理的，目标glycodendrimers可以合成和评估其抗艾滋病毒特性的项目的时间范围内。这项拟议中的研究试图通过提供专门针对病毒gp 120的先导化合物来填补抗艾滋病毒药物库中的空白。相关性：在美国，有850 000 - 950 000艾滋病毒感染者，另有180 000 - 280 000人不知道他们是艾滋病毒阳性。由于病毒耐药性引起的不良副作用和药物有效性降低，开发新的抗HIV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种新的抗艾滋病毒药物。

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.