Novel Carbohydrate Probes for gp120-GalCer Recognition

描述(申请人提供)：出现对该病毒具有抗药性的病毒株 治疗艾滋病毒的标准方案被称为高效抗逆转录病毒疗法(HAART)，这导致了人们对针对艾滋病毒感染的不同阶段的治疗方法的兴趣。HIV包膜糖蛋白和碳水化合物β-半乳糖基神经酰胺(GalCer)之间的相互作用被认为是传染性的早期步骤。这一提议的长期目标是阐明这一识别过程的分子基础。这一信息与gp120-GalCer结合的有效抑制剂的开发有关，并最终与新型艾滋病毒进入抑制剂有关。我们的工作假设是GalCer通过糖和脂段更远端区域的关键接触点与gp120结合，神经酰胺的中央极性头部段主要作为支架，控制糖和脂段的相对空间位置。这个模型是基于现有的结构-活性数据，以及我们的观察结果，即相对简单的O-糖苷与gp120的结合比其C-糖苷类似物(即。糖苷氧被CH2取代)。为了询问这些构象要求，我们设计了O-和C-半乳糖脂探针，其中脂质样本相对于半乳糖片段在构象空间的不同区域。 O-糖苷结构将通过标准的糖苷化程序制备，而C- 通过我们实验室开发的一种新的C-糖苷化方法来合成糖苷类化合物。这个 这些分子的构象和gp120结合性质将与马德里CSLC的Jesse Jimenez Barbero博士和UC Davis的Jacquelyn Gervay-海牙教授合作确定。假设预先组织了更多结合的配体将比没有预先组织的配体更活跃，我们预计可以更清楚地了解生物活性构象。从更广泛的角度来看，这项研究承诺在碳水化合物合成和构象的新领域做出基本贡献。这一信息将为将这些结构活性探针扩展到蛋白质-碳水化合物识别的其他问题奠定基础。

DESCRIPTION (provided by applicant): The emergence of viral strains that are resistant to the standard regimen for treatment of HIV, known as highly active anti-retroviral therapy (HAART), has led to interest in therapeutic approaches that target alternative stages of HIV infectivity. The interaction between the HIV envelope glycoprotein and the carbohydrate beta -galactosyl ceramide (GalCer) has been implicated as an early step in infectivity. The long term goal of this proposal is the elucidation of the molecular basis of this recognition process. This information is relevant to the development of potent inhibitors of gp120-GalCer binding, and ultimately, to novel HIV entry inhibitors. Our working hypothesis is that GalCer binds gp120 through key contact points in the sugar and the more distal region of the lipid segment, and that the central polar head segment of the ceramide acts primarily as a scaffold that controls the relative spatial positions of the sugar and lipid regions. This model is based on existing structure-activity data, and our observation that a relatively simple O-glycoside, binds gp120 considerably more strongly than its C-glycoside analog (ie. The glycosidic oxygen is replaced by CH2). To interrogate these conformational requirements, we have designed O-and C- galacto-lipid probes in which the lipid samples different regions of conformational space, relative to the galactose segment. The O-glycoside structures will be prepared by standard glycosidation procedures, and the C- glycosides via a novel C-glycosidation methodology that was developed in our laboratory. The conformational and gp120 binding properties of these molecules will be determined in collaboration with Dr. Jesus Jimenez Barbero (CSlC, Madrid) and Professor Jacquelyn Gervay-Hague (UC Davis). On the assumption that ligands that are more preorganized for binding will be more active, than ones that are not, we expect to obtain a clearer picture of the bioactive conformation. On a broader note, this study promises fundamental contributions in new areas of carbohydrate synthesis and conformation. This information will lay the groundwork for the extension of these structure activity probes to other problems in protein-carbohydrate recognition.