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.
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.
|Wang, Peng; Kouyoumdjian, Hovig; Zhu, David C et al. (2015) Heparin nanoparticles for ? amyloid binding and mitigation of ? amyloid associated cytotoxicity. Carbohydr Res 405:110-4|
|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-?(1-15) glycopeptides, new biomarkers for Alzheimer's disease. Chem Commun (Camb) 50:15067-70|
|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|
|Sheng, Juzheng; Xu, Yongmei; Dulaney, Steven B et al. (2012) Uncovering biphasic catalytic mode of C5-epimerase in heparan sulfate biosynthesis. J Biol Chem 287:20996-1002|
|Tiruchinapally, Gopinath; Yin, Zhaojun; El-Dakdouki, Mohammad et al. (2011) Divergent heparin oligosaccharide synthesis with preinstalled sulfate esters. Chemistry 17:10106-12|
|Gilbert, Wasonga; Youlin, Zeng; Xuefei, Huang (2011) Pre-activation based stereoselective glycosylations: Stereochemical control by additives and solvent. Sci China Chem 54:66-73|
|Wang, Yanyan; El-Boubbou, Kheireddine; Kouyoumdjian, Hovig et al. (2010) Lipoic acid glyco-conjugates, a new class of agents for controlling nonspecific adsorption of blood serum at biointerfaces for biosensor and biomedical applications. Langmuir 26:4119-25|
|Wang, Zhen; Xu, Yongmei; Yang, Bo et al. (2010) Preactivation-based, one-pot combinatorial synthesis of heparin-like hexasaccharides for the analysis of heparin-protein interactions. Chemistry 16:8365-75|
|Lu, Xiaowei; Kamat, Medha N; Huang, Lijun et al. (2009) Chemical synthesis of a hyaluronic acid decasaccharide. J Org Chem 74:7608-17|
Showing the most recent 10 out of 21 publications