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    Developing a selective inhibitor of human Golgi alpha-mannosidase II and carbohydrate based vaccines targeting bioterrorism weapons

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    Date
    2007-08
    Author
    Zhong, Wei
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    Abstract
    Inhibition of the mannose trimming enzyme human Golgi ±-mannosidase II (HGMII) that acts late in the N-glycan processing pathway, provides one route to blocking the oncogene-induced changes in cell surface oligosaccharide structures. HGMII selectively cleaves ±(1->3) and ±(1->6) mannosyl residues present in its natural substrate GlcNAcMan5GlcNAc2. It has been proposed that HGMII has an extended binding site recognizing a large part of the oligosaccharide. To probe the substrate requirements of HGMII, we have synthesized a range of part-structures of GlcNAcMan5GlcNAc2 and determined kinetic parameters for hydrolysis by HGMII. Mannostatin A is a potent inhibitor of HGMII. The thiomethyl moiety is a feature that is not observed in any other glycosidase inhibitors. It has been proposed that the sulfur atom and e-CH3 group of methionine residues are involved in several different interactions important for protein stability. To probe the interactions of the thiomethyl function with dGMII, Mannostatin B and analogs, which contain hydroxyl, methoxy or deoxy, respectively instead of the thiomethyl moiety, were prepared. The ability of the compounds to inhibit dGMII has been examined. The glycoprotein BclA, an important constituent of the exosporium of Bacillus anthracis spores, is substituted with an oligosaccharide composed of a ²-L-rhamnoside substituted with anthrose, a potential species-specific marker for B. anthracis. To study the antigenicity of anthrose, syntheses of an anthrose-containing trisaccharide and a series of structurally related analogues were developed. Serum antibodies of rabbits immunized with live or irradiated spores of B. anthracis Sterne 34F2 were able to recognize the synthetic trisaccharide-mcKLH conjugate. Inhibition using the trisaccharide analogues demonstrated that the isovaleric acid moiety of anthrose is an important structural motif for antibody recognition. Francisella tularensis, the etiologic agent of tularemia in humans and animals, has been classified as a top-priority bio-terrorism agent. Recently, the structure of the lipopolysaccharide of F. tularensis was determined. We developed a highly convergent synthesis of a number of truncated structures to determine the smallest part structure of the core oligosaccharide, which can elicit antibodies that recognize LPS from F. tularensis. Such a structure will be attractive to be further developed as a vaccine candidate for tularemia.
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    http://purl.galileo.usg.edu/uga_etd/zhong_wei_200708_phd
    http://hdl.handle.net/10724/24343
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    • University of Georgia Theses and Dissertations

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