Studies of naturally occurring structurally modified carbohydrates

描述（由申请人提供）：碳水化合物的结构修饰是自然界中普遍存在的现象。例如，在许多蛋白聚糖、糖蛋白和糖脂中存在的硫代碳水化合物被认为在特定的分子识别过程中起重要作用。此外，唾液酸单糖的修饰，如磺化、磷酸化、甲基化、乙酰化和乳酸化，导致在自然界中观察到50多种不同的唾液酸形式。然而，由于技术上难以获得均匀的结构修饰碳水化合物和糖缀合物，因此对这些碳水化合物修饰的构效关系知之甚少。该项目的长期目标是开发新的化学-酶方法，通过自然发生的修饰来合成结构明确的碳水化合物，并更好地了解它们的生物学作用。在目前的批准期内，我们将把重点放在含唾液酸的结构上。

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.