Studies of naturally occurring structurally modified carbohydrates

描述(申请人提供)：碳水化合物的结构修饰是自然界中的一种常见现象。例如，存在于许多蛋白多糖、糖蛋白和糖脂中的硫化碳水化合物被认为在特定的分子识别过程中发挥着重要作用。此外，对唾液酸单糖的修饰，如硫化、磷酸化、甲基化、乙酰化和乳酸化，导致观察到自然界中50多种不同的唾液酸形式。然而，由于获得均一结构修饰的碳水化合物和糖共轭化合物的技术困难，人们对这些碳水化合物修饰的结构-活性关系(SAR)知之甚少。该计划的长期目标是开发新的化学-酶方法，用于合成具有自然修饰的结构定义的碳水化合物，并更好地了解它们的生物学作用。在目前的授权期内，我们将重点研究含唾液酸的结构。 唾液酸是一类带负电荷的9碳糖类，主要被发现为脊椎动物糖结合物中最外层的碳水化合物。唾液酸作为其他生物分子的前线，在多种生理和病理过程中发挥着关键作用，包括细胞-细胞相互作用、信号传递、炎症和感染等。基于唾液酸的识别过程被认为与唾液酸的精细结构、与唾液酸连接的碳水化合物结构以及它们之间的连接类型密切相关。我们建议用化学酶法合成一个包含大多数这些自然产生的不同结构的唾液酸苷文库，并将其应用于蛋白质-碳水化合物相互作用的研究。该方案的具体目标是：1.化学合成各种唾液酸类似物及其前体；2.酶法合成CMP-唾液酸衍生物和唾液酸苷文库；3.利用唾液酸识别蛋白研究获得的唾液酸苷文库的构效关系(SAR)。由于唾液酸是许多生理和病理过程中的关键元素，完成这些研究还可能有助于发现和开发新的治疗人类疾病的方法，如癌症、炎症性疾病、感染性疾病和其他致病疾病。

DESCRIPTION (provided by applicant): Structural modification of carbohydrates is a common phenomenon in nature. For example, sulfated carbohydrates presented in a number of proteoglycans, glycoproteins, and glycolipids are believed to play important roles in specific molecular recognition processes. Furthermore, modifications of sialic acid monosaccharides, such as sulfation, phosphorylation, methylation, acetylation, and lactylation, lead to the observation of more than 50 different sialic acid forms in nature. Little is known, however, about the SAR (structure-activity relationship) of these carbohydrate modifications due to technical difficulties in obtaining homogenous structurally modified carbohydrates and glycoconjugates. The long-term goal of this program is to develop novel chemo-enzymatic methods for synthesizing structurally defined carbohydrates with naturally occurring modifications and to provide better understanding of their biological roles. In the current granting period, we will focus our efforts on the sialic acid-containing structures. Sialic acids are a family of negatively charged 9-carbon sugars that have been predominantly found as the outermost carbohydrates of vertebrate glycoconjugates. As the frontline encountered by other biomolecules, sialic acids play pivotal roles in a variety of physiological and pathological processes, including cell-cell interaction, signaling, inflammation, and infection etc. The sialic acid-based recognition processes are believed to be closely related to the fine structures of the sialic acids, the carbohydrate structures linked to the sialic acids, and the types of the linkages in between. We propose to chemo-enzymatically synthesize a sialoside library containing the majority of these naturally occurring diverse structures and apply it in protein-carbohydrate interaction studies. The specific aims of the proposal are to: 1. chemically synthesize diverse sialic acid analogs and their precursors; 2. enzymatically synthesize CMP-sialic acid derivatives and a sialoside library; 3. study structure-activity relationship (SAR) of the obtained sialoside library using sialic acid-recognizing proteins. As sialic acids are key elements in many physiological and pathological processes, accomplishing the proposed studies may also facilitate the discovery and development of new therapeutics for human diseases such as cancer, inflammatory, infectious, and other pathogenic diseases.