Novel Carbohydrate Probes for gp120-GalCer Recognition

用于 gp120-GalCer 识别的新型碳水化合物探针

• 批准号: 6773122
• 负责人: DAVID R. MOOTOO
• 金额: $ 8.61万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6773122
• 关键词: HIV envelope protein gp120; biotechnology; carbohydrate structure; ceramides; chemical models; chemical synthesis; conformation; glycosides; molecular probes; protein binding; technology /technique development; virus infection mechanism

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.

描述（由申请人提供）：出现了对 用于治疗HIV标准方案，称为高效抗逆转录病毒疗法（HAART），已经引起了对靶向HIV感染的替代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感染性的早期步骤。该建议的长期目标是阐明这种识别过程的分子基础。该信息与gp 120-GalCer结合的有效抑制剂的开发相关，并最终与新型HIV进入抑制剂相关。我们的工作假设是，GalCer结合gp 120通过关键接触点的糖和更远的区域的脂质段，和中央极性头段的神经酰胺主要作为一个支架，控制相对的空间位置的糖和脂质区域。该模型基于现有的结构-活性数据，以及我们的观察结果，即相对简单的O-糖苷比其C-糖苷类似物（即O-糖苷）更强地结合gp 120。糖苷氧被CH 2取代）。为了询问这些构象的要求，我们设计了O-和C-半乳糖-脂质探针，其中脂质样品的构象空间的不同区域，相对于半乳糖段。 O-糖苷结构将通过标准糖苷化程序制备，并且C-糖苷结构将通过标准糖苷化程序制备。 通过我们实验室开发的新的C-糖苷化方法合成糖苷。的 这些分子的构象和gp 120结合性质将与Jesus Jimenez Barbero博士（CSIC，马德里）和Jacquelyn Gervay-Hague教授（UC Davis）合作确定。在假设的配体，更预先组织的结合将更活跃，比那些没有，我们期望获得一个更清晰的图像的生物活性构象。从更广泛的角度来看，这项研究有望在碳水化合物合成和构象的新领域做出重要贡献。这些信息将为这些结构活性探针扩展到蛋白质-碳水化合物识别中的其他问题奠定基础。