title: Synthesis of an S-Linked α(2→8) GD3 Antigen and Evaluation of the Immunogenicity of Its Glycoconjugate.
abstract: Replacing the interglycosidic oxygen atom of oligosaccharides with a nonhydrolyzable sulfur atom has attracted significant interest because it provides opportunities for developing new glycoconjugate vaccines. Herein, a stereocontrolled and highly convergent method to synthesize a non-reducing-end inter-S-glycosidic variant of the GD3 antigen (S-linked α(2→8) GD3) that is resistant to enzymatic hydrolysis is reported. The key steps in the synthesis are a regio- and stereoselective α(2→3) sialylation of a lactoside acceptor with a C8-iodide-derivatized sialyl donor and an anomeric S-alkylation, which enable stereoselective construction of a terminal S-linked α(2→8) disialyl residue. The sulfhydryl-reactive maleimide group was used as the linker for the well-defined conjugation of these antigens to the immunogenic protein keyhole limpet hemocyanin (KLH). Groups of mice were immunized with the GD3-KLH and S-linked GD3-KLH glycoconjugates in the presence of complete Freund's adjuvant. Microarray analysis of the sera showed the promise of the S-linked GD3-KLH vaccine: it stimulated a high immunoglobulin G response against S-linked GD3 and cross-reactivity with the O-linked GD3 antigen was low. The activity of the S-linked GD3-KLH vaccine was comparable to that of the O-linked GD3-KLH vaccine, which highlighted the effectiveness of generating glycoconjugate vaccines and immunotherapies by relatively simple means.
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu-, 300, Taiwan.
authors.forename: Ting-Chun
authors.initials: TC
authors.lastname: Kuan
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu-, 300, Taiwan.
authors.forename: Hsin-Ru
authors.initials: HR
authors.lastname: Wu
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu-, 300, Taiwan.
authors.forename: Avijit K
authors.initials: AK
authors.lastname: Adak
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu-, 300, Taiwan.
authors.forename: Ben-Yuan
authors.initials: BY
authors.lastname: Li
authors.affiliation: Department of Chemistry, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Liang
authors.affiliation: Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Jung-Tung
authors.initials: JT
authors.lastname: Hung
authors.affiliation: Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Shih-Pin
authors.initials: SP
authors.lastname: Chiou
authors.affiliation: Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Yu
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu-, 300, Taiwan.
authors.forename: Jih Ru
authors.initials: JR
authors.lastname: Hwu
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu-, 300, Taiwan.
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Lin
mesh_terms: D000818:Animals; D000941:Antigens / Q000737:chemistry / Q000276:immunology; D005732:Gangliosides / Q000737:chemistry*; D006001:Glycoconjugates / Q000138:chemical synthesis / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006433:Hemocyanins / Q000737:chemistry* / Q000276:immunology; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008301:Maleimides / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014614:Vaccines, Synthetic / Q000276:immunology; D014734:Vibrio cholerae / Q000201:enzymology
chemical_list: D000941:Antigens; D005732:Gangliosides; D006001:Glycoconjugates; D007074:Immunoglobulin G; D008301:Maleimides; D013438:Sulfhydryl Compounds; D014614:Vaccines, Synthetic; C043592:maleimide; C026226:ganglioside, GD3; D006433:Hemocyanins; D009439:Neuraminidase; C032808:keyhole-limpet hemocyanin
keywords: alpha-sialylation; carbohydrates; enzyme catalysis; glycosylation; sialic acids