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艾滋病毒表面蛋白gp120结合的糖树状大分子，并阻止随后与宿主细胞的相互作用导致病毒进入。Gp120以异源三聚体的形式存在于HIV与膜蛋白gp41结合的表面。Gp120/gp41复合体与细胞表面的CD4结合后，发生构象变化，暴露出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的辅助受体，这加强了病毒与宿主细胞的相互作用，允许随后的gp41融合、孔形成，并最终进入病毒。据报道，病毒的融合/进入过程是合作的，需要多个副本的CD4、宿主细胞共受体和gp41/gp120异源三聚体的聚集。由于病毒融合/进入过程的多价性，假设糖树状大分子将能够同时与多个拷贝的gp120结合，防止病毒进入。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。这一假设将通过四个具体目标的实现来检验。SA#1描述了可互换的树枝状大分子连接体和差异支化核心的合成。SA#2概述了离散碳水化合物-连接物的合成，为偶联到支化的树枝状大分子核心做好了准备。SA#3描述了各种支化糖树状大分子的构建，以评估与gp120最佳结合所需的特定结构特征以及病毒感染性的抑制，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，目标糖树枝状大分子可以在项目的时间框架内合成并评估其抗艾滋病毒性能。这项拟议的研究试图通过提供专门针对病毒gp120的先导化合物来填补抗艾滋病毒药物武器库的空白。相关性：在美国，有85万至95万艾滋病毒感染者，还有18万至28万人不知道自己是艾滋病毒阳性者。由于病毒耐药性导致的不良副作用和药物有效性的降低，抗HIV新药的开发对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型的抗艾滋病毒药物。

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.