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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM076360-05
Application #
7752560
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
2006-01-01
Project End
2010-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$272,570
Indirect Cost
Name
University of California Davis
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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