Heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans play important roles in many physiological and pathological events, such as cell division, inflammation, neuronal development, and cancer metastasis. Naturally existing HS and CS display a diverse range of sulfation patterns. While this structural diversity bestows HS and CS with the ability to interact with many proteins, it greatly hinders the ability to decipher their structure-function relationships. In order to dramatically advance an understanding of the biological functions of glycosaminoglycans, it is critical to access large, structurally diverse libraries of HS and CS oligosaccharides bearing well-defined sulfation sequences. To date, synthetic methodologies toward HS and CS are mostly target oriented, resulting in only small sets of oligosaccharides. Furthermore, it remains difficult to prepare HS and CS sequences longer than a dodecasaccharide. To address these challenges, three research groups with strong, complementary expertise in HS and CS synthesis and biology have joined forces to accomplish the following aims.
In Aim 1, new synthetic strategies are proposed to accelerate the synthesis of HS oligosaccharides. Methodologies will be developed to prepare the first comprehensive library of 256 HS tetrasaccharides representing all of the possible 2-O, 6-O and N sulfation motifs, along with a library of structurally diverse 3-O sulfated tetrasaccharides and HS hexasaccharides.
In Aim 2, we propose new efficient, cost-effective routes to access the first comprehensive library of CS tetrasaccharides bearing all of the possible mammalian sulfation sequences.
In Aim 3, HS/CS oligosaccharide-based polymers and head-to-tail multimers will be prepared to enable access to structures containing homogeneously sulfated glycans with sizes approaching natural polysaccharides. These mimetics will possess similar domain structures and multivalent properties found in naturally existing CS and HS polysaccharides.
In Aim 4, we will validate the hypothesis that our molecules can recapitulate the biological functions of HS and CS polysaccharides using well-established assays, including anticoagulation, neuronal growth, and protein-binding assays. Furthermore, we will explore the potential for these molecules to selectively target a clinically important family of proteins, the fibroblast growth factors. Together, this project will provide faster, more affordable syntheses of HS and CS, greatly expand the chemical space currently accessible by synthesis, enable the first direct, in-depth comparisons between HS and CS, and provide novel agents to control the activities of these biomedically important molecules.

Public Health Relevance

Heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans play important roles in many biological events and have strong therapeutic potential. The overall goals of this project are to develop faster, more affordable syntheses of large libraries of HS and CS oligosaccharides, as well as glycomimetics that recapitulate the activities of the natural polysaccharides. Together, these studies are expected to advance an understanding of the biological functions of GAGs, unlock their 'sulfation code,' and help validate GAGs as novel drugs and drug targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01GM116262-02
Application #
9102117
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Marino, Pamela
Project Start
2015-07-01
Project End
2019-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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Ramadan, Sherif; Yang, Weizhun; Zhang, Zeren et al. (2017) Synthesis of Chondroitin Sulfate A Bearing Syndecan-1 Glycopeptide. Org Lett 19:4838-4841
Yang, Weizhun; Ramadan, Sherif; Yang, Bo et al. (2016) Homoserine as an Aspartic Acid Precursor for Synthesis of Proteoglycan Glycopeptide Containing Aspartic Acid and a Sulfated Glycan Chain. J Org Chem 81:12052-12059
Yang, Weizhun; Yoshida, Keisuke; Yang, Bo et al. (2016) Obstacles and solutions for chemical synthesis of syndecan-3 (53-62) glycopeptides with two heparan sulfate chains. Carbohydr Res 435:180-194
Dulaney, Steven B; Xu, Yongmei; Wang, Peng et al. (2015) Divergent Synthesis of Heparan Sulfate Oligosaccharides. J Org Chem 80:12265-79