Synthesis of Carbohydrate Immunostimulating Agents

碳水化合物免疫刺激剂的合成

• 批准号: 7145928
• 负责人: David Y Gin
• 金额: $ 27.75万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145928
• 关键词: chemical conjugate; chemical structure function; chemical synthesis; covalent bond; drug design /synthesis /production; glycosylation; immunomodulators; method development; mucins; oligosaccharides; peptides; tumor antigens

DESCRIPTION (provided by applicant): A research program devoted to the development of new methods for the synthesis of biologically important complex oligosaccharides and glycoconjugates is proposed. Several new methods for glycosidic bond formation will be developed in this granting period. The first is the establishment of the concept of sulfoxide covalent catalysis in the context of dehydrative glycosylation employing 1-hydroxy glycosyl donors. The second reaction is an oxidative glycosylation reaction employing glycal donors. Through the use of hypervalent l(lll) reagents, we intend to establish C2-acyloxyglycosylation as an efficient glycal assembly process for complex carbohydrate synthesis. Investigations into the scope, mechanism, and stereochemical determinants in these new reactions should lead to a series of powerful glycosylation methods that can be applied to the synthesis of natural and non-natural oligosaccharides that are of importance to biology and human medicine. With the use of our glycosylation methodologies, we are in a unique position to perform the first systematic structure-function studies of QS-21 A, a potent immunostimulatory adjuvant used in more than 80 recent and ongoing vaccine clinical trials. Following our recent chemical synthesis of QS-21 A, the design and synthesis of several structurally modified/truncated analogs of QS-21 A is proposed to generate more potent adjuvants and to probe its unknown mechanism of immunostimulatory activity through SAR studies. We also propose to develop a new strategy for the site selective covalent conjugation of complex carbohydrates with peptides. The efficient synthesis of this class of glycoconjugates will allow for the preparation of diverse glycosylated mucin fragments not only for fundamental studies on mucin glycopeptide architecture, but also for the design of more hydrolytically stable mucin-associated subunit antigens for vaccine therapy. The full development of this research program will expand the repertoire of available carbohydrate synthesis methods and facilitate access to complex carbohydrate immunostimulants for immunological evaluation, mechanistic investigation, and clinical application.

描述（由申请人提供）：提出了一项研究计划，用于开发新方法，用于合成生物学上重要的复杂寡糖和糖缀合物。在本授予期间将开发几种糖苷债券形成的新方法。首先是在使用1-羟基糖基供体的脱水糖基化背景下，建立硫氧化物共价催化的概念。第二个反应是采用糖供体的氧化糖基化反应。通过使用高价值L（LLL）试剂，我们打算建立C2-乙酰羟基糖基化，作为复杂碳水化合物合成的有效甘氨酸组装过程。这些新反应中对范围，机制和立体化学决定因素的研究应导致一系列强大的糖基化方法，这些方法可用于合成对生物学和人类医学至关重要的自然和非天然寡糖的合成。通过使用我们的糖基化方法，我们处于独特的位置，可以对QS-21 A进行首次系统的结构功能研究，这是在最近80多种最近正在进行的疫苗临床试验中使用的有效的免疫刺激辅助物。在我们最近对QS-21 A的化学合成之后，提出了几种结构修饰/截断的QS-21 A的设计和合成，以通过SAR研究来产生更有效的佐剂，并探究其未知的免疫抑制活性机制。我们还建议制定一种新的策略，以选择将复杂碳水化合物与肽的选择性共轭共轭。这类糖缀合物的有效合成将允许制备多种糖基化的粘蛋白片段，不仅是针对粘蛋白糖肽结构的基本研究，还可以设计更稳定的粘蛋白粘蛋白相关亚基抗原用于疫苗治疗。该研究计划的全面发展将扩大可用碳水化合物合成方法的曲目，并促进获得复杂的碳水化合物免疫刺激剂，以进行免疫学评估，机械研究和临床应用。