Heparin (HP) and heparan sulfate (HS) participate in a wide variety of physiological and pathological events, including viral infection, blood coagulation, cell differentiation and cancer metastasis. Their multi-faceted biological activities suggest that there are tremendous potential in using HP/HS as novel therapeutics. However, access to structurally well defined HP/HS oligosaccharides has been very difficult, which severely hinders the establishment of detailed structure activity relationships. In this application, a new synthetic strategy based on chemoenzymatic methods is proposed to acquire a panel of structurally diverse, precisely designed HP/HS oligosaccharides.
In aim 1, chemical synthesis of HP/HS oligosaccharides using the pre-activation based one pot glycosylation method will be studied. The target structures will be systematically varied to include both glucuronic acid and iduronic acid in the backbone, diversified O-sulfation patterns, and differentiated nitrogen modifications. Oligosaccharides with sizes approaching those of polysaccharides will also be assembled. The pre-activation based one pot glycosylation method is highly advantageous as it allows rapid synthesis of HP/HS oligosaccharides with great sequence diversity.
In aim 2, chemical synthesis will be integrated with enzymatic modification. The chemically prepared HP/HS oligosaccharides will be modified by sulfo transferases in a divergent manner, thus further increasing their sequence diversity. Moreover, glycosyl transferases will be used to elongate the functionalized HP/HS oligosaccharides, providing access to oligosaccharides composed of distinct domains.
In aim 3, the precisely designed HP/HS oligosaccharides will be assayed for their heparanase inhibitory activities as well as growth factor and platelet factor 4 binding. The effects of backbone sequence, nitrogen substitution and O-sulfation will be evaluated to develop a highly specific heparanase inhibitor with low undesired biological interactions. The results of the proposed studies will establish the basis and tools for the structure-function relationship studies of HP/HS, leading to exciting opportunities for discovery of HP/HS based novel therapeutic agents.

Public Health Relevance

Heparin (HP) and heparan sulfate (HS) interact with many proteins involved in important biological processes such as cell differentiation, pathogen infection, cancer metastasis, and blood coagulation. The long term goal of this project is to prepare structurally well defined HP/HS oligosaccharides, and use these precisely designed compounds to establish the structure and activity relationship of HP/HS. This can potentially lead to the development of novel therapeutic agents against blood coagulation, cancer and viral infection.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Michigan State University
Schools of Arts and Sciences
East Lansing
United States
Zip Code
Wang, Peng; Lo Cascio, Filippa; Gao, Jia et al. (2018) Binding and neurotoxicity mitigation of toxic tau oligomers by synthetic heparin like oligosaccharides. Chem Commun (Camb) 54:10120-10123
Hossaini Nasr, Seyedmehdi; Tonson, Anne; El-Dakdouki, Mohammad H et al. (2018) Effects of Nanoprobe Morphology on Cellular Binding and Inflammatory Responses: Hyaluronan-Conjugated Magnetic Nanoworms for Magnetic Resonance Imaging of Atherosclerotic Plaques. ACS Appl Mater Interfaces 10:11495-11507
Nasr, Seyedmehdi Hossaini; Kouyoumdjian, Hovig; Mallett, Christiane et al. (2018) Detection of ?-Amyloid by Sialic Acid Coated Bovine Serum Albumin Magnetic Nanoparticles in a Mouse Model of Alzheimer's Disease. Small 14:
Yang, Bo; Yang, Weizhun; Ramadan, Sherif et al. (2018) Pre-activation Based Stereoselective Glycosylations. European J Org Chem 2018:1075-1096
Yang, Weizhun; Ramadan, Sherif; Orwenyo, Jared et al. (2018) Chemoenzymatic synthesis of glycopeptides bearing rare N-glycan sequences with or without bisecting GlcNAc. Chem Sci 9:8194-8206
Ramadan, Sherif; Yang, Weizhun; Zhang, Zeren et al. (2017) Synthesis of Chondroitin Sulfate A Bearing Syndecan-1 Glycopeptide. Org Lett 19:4838-4841
Xu, Yongmei; Chandarajoti, Kasemsiri; Zhang, Xing et al. (2017) Synthetic oligosaccharides can replace animal-sourced low-molecular weight heparins. Sci Transl Med 9:
Yang, Weizhun; Yang, Bo; Ramadan, Sherif et al. (2017) Preactivation-based chemoselective glycosylations: A powerful strategy for oligosaccharide assembly. Beilstein J Org Chem 13:2094-2114
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
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

Showing the most recent 10 out of 38 publications