A major obstacle to advances in glycobiology and glyco-medicine is the lack of pure and structurally well-defined carbohydrates and glycoconjugates. In many cases, well-defined oligosaccharides can only be obtained by chemical synthesis. Unfortunately, no general method is available for the preparation of complex carbohydrates of biological importance and one of the main stumbling blocks is the lack of a reliable methodology for the stereoselective formation of 1,2-cis-glycosides. Our preliminary studies have shown that a glycosyl donor substituted with a chiral auxiliary, such as a (S)-(phenylthiomethyl)benzyl ether, can be employed for the stereoselective introduction of 1,2-cis glycosides such as a-glucosides and a-galactosides. Neighboring group participation by the chiral auxiliary leads to a quasi-stable anomeric sulfonium ion, which due to steric and electronic factors is formed as a trans-decalin ring system. Displacement of the ?-sulfonium ion by a hydroxyl leads to the stereoselective introduction of a-glycosides.
The aim of this application is to further develop the synthetic methodology and apply it to the preparation of oligosaccharides that have the potential to be developed as vaccines. The compatibility of the auxiliaries with commonly used glycosylation protocols and protecting group manipulations will be established. The auxiliary based methodology will be extended to the introduction of a wide variety of 1,2-cis-glycosides. A new generation of chiral auxiliary will be developed with improved properties such better acid stability, selective removable in the presence of sensitive protecting groups, and compatible with highly reactive glycosyl donors. Finally, the new methodology will be applied to the synthesis of oligosaccharides derived from Francisella tularensis and Bacillus anthracis, which are category-A bio-terrorism agents. Immunological experiments will be performed to establish whether the synthetic compounds can be employed as vaccine candidates.

Public Health Relevance

A major obstacle to advances in glycobiology and glyco-medicine is the lack of pure and structurally well-defined carbohydrates. It is proposed to develop new synthetic methodologies for the preparation for well-defined complex carbohydrates. The new methodology will be applied to the preparation of oligosaccharides derived from pathogens, which are classified as category-A bio- terrorism agents. Immunological experiments will be performed to establish whether the synthetic compounds can be employed as vaccine candidates. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM065248-05
Application #
7461340
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Marino, Pamela
Project Start
2004-01-01
Project End
2012-07-31
Budget Start
2008-08-19
Budget End
2009-07-31
Support Year
5
Fiscal Year
2008
Total Cost
$368,750
Indirect Cost
Name
University of Georgia
Department
Type
Organized Research Units
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Fang, Tao; Gu, Yi; Huang, Wei et al. (2016) Mechanism of Glycosylation of Anomeric Sulfonium Ions. J Am Chem Soc 138:3002-11
Huang, Wei; Gao, Qi; Boons, Geert-Jan (2015) Assembly of a Complex Branched Oligosaccharide by Combining Fluorous-Supported Synthesis and Stereoselective Glycosylations using Anomeric Sulfonium Ions. Chemistry 21:12920-6
Gagarinov, Ivan A; Fang, Tao; Liu, Lin et al. (2015) Synthesis of Staphylococcus aureus Type 5 trisaccharide repeating unit: solving the problem of lactamization. Org Lett 17:928-31
Dhamale, Omkar P; Zong, Chengli; Al-Mafraji, Kanar et al. (2014) New glucuronic acid donors for the modular synthesis of heparan sulfate oligosaccharides. Org Biomol Chem 12:2087-98
Zong, Chengli; Venot, Andre; Dhamale, Omkar et al. (2013) Fluorous supported modular synthesis of heparan sulfate oligosaccharides. Org Lett 15:342-5
Mo, Kai-For; Li, Xiuru; Li, Huiqing et al. (2012) Endolysins of Bacillus anthracis bacteriophages recognize unique carbohydrate epitopes of vegetative cell wall polysaccharides with high affinity and selectivity. J Am Chem Soc 134:15556-62
Boltje, Thomas J; Zhong, Wei; Park, Jin et al. (2012) Chemical synthesis and immunological evaluation of the inner core oligosaccharide of Francisella tularensis. J Am Chem Soc 134:14255-62
Fang, Tao; Mo, Kai-For; Boons, Geert-Jan (2012) Stereoselective assembly of complex oligosaccharides using anomeric sulfonium ions as glycosyl donors. J Am Chem Soc 134:7545-52
Boltje, Thomas J; Kim, Jin-Hwan; Park, Jin et al. (2011) Stereoelectronic effects determine oxacarbenium vs ýý-sulfonium ion mediated glycosylations. Org Lett 13:284-7
Saile, Elke; Boons, Geert-Jan; Buskas, Therese et al. (2011) Antibody responses to a spore carbohydrate antigen as a marker of nonfatal inhalation anthrax in rhesus macaques. Clin Vaccine Immunol 18:743-8

Showing the most recent 10 out of 27 publications