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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072667-08
Application #
8266436
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2005-03-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$297,801
Indirect Cost
$71,883
Name
Michigan State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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
Wang, Peng; Kouyoumdjian, Hovig; Zhu, David C et al. (2015) Heparin nanoparticles for β amyloid binding and mitigation of β amyloid associated cytotoxicity. Carbohydr Res 405:110-4
Dulaney, Steven B; Xu, Yongmei; Wang, Peng et al. (2015) Divergent Synthesis of Heparan Sulfate Oligosaccharides. J Org Chem 80:12265-79
Lu, Xiaowei; Huang, Xuefei (2015) Design and syntheses of hyaluronan oligosaccharide conjugates as inhibitors of CD44-Hyaluronan binding. Glycoconj J 32:549-56
Zhou, Wen; Hsieh, Po-Hung; Xu, Yongmei et al. (2015) Design and synthesis of active heparan sulfate-based probes. Chem Commun (Camb) 51:11019-21
Yoshida, Keisuke; Yang, Bo; Yang, Weizhun et al. (2014) Chemical synthesis of syndecan-3 glycopeptides bearing two heparan sulfate glycan chains. Angew Chem Int Ed Engl 53:9051-8
Wang, Peng; Nilsson, Jonas; Brinkmalm, Gunnar et al. (2014) Synthesis aided structural determination of amyloid-β(1-15) glycopeptides, new biomarkers for Alzheimer's disease. Chem Commun (Camb) 50:15067-70
Wasonga, Gilbert; Tatara, Yota; Kakizaki, Ikuko et al. (2013) Synthesis of N-acetyl Glucosamine Analogs as Inhibitors for Hyaluronan Biosynthesis. J Carbohydr Chem 32:392-409
Xu, Yongmei; Wang, Zhen; Liu, Renpeng et al. (2012) Directing the biological activities of heparan sulfate oligosaccharides using a chemoenzymatic approach. Glycobiology 22:96-106
Yang, Bo; Yoshida, Keisuke; Yin, Zhaojun et al. (2012) Chemical synthesis of a heparan sulfate glycopeptide: syndecan-1. Angew Chem Int Ed Engl 51:10185-9

Showing the most recent 10 out of 29 publications