title: Synthesis and immunological studies of linear oligosaccharides of β-glucan as antigens for antifungal vaccine development.
abstract: Antifungal vaccines have recently engendered considerable excitement for counteracting the resurgence of fungal infections. In this context, β-glucan, which is abundantly expressed on all fungal cell surfaces, functionally necessary for fungi, and immunologically active, is an attractive target antigen. Aiming at the development of effective antifungal vaccines based on β-glucan, a series of its oligosaccharide derivatives was designed, synthesized, and coupled with a carrier protein, keyhole limpet hemocyanin (KLH), to form new semisynthetic glycoconjugate vaccines. In this article, a convergent and effective synthetic strategy using preactivation-based iterative glycosylation was developed for the designed oligosaccharides. The strategy can be widely useful for rapid construction of large oligo-β-glucans with shorter oligosaccharides as building blocks. The KLH conjugates of the synthesized β-glucan hexa-, octa-, deca-, and dodecasaccharides were demonstrated to elicit high titers of antigen-specific total and IgG antibodies in mice, suggesting the induction of functional T cell-mediated immunity. Moreover, it was revealed that octa-, deca-, and dodeca-β-glucans were much more immunogenic than the hexamer and that the octamer was the best among these. The results suggested that the optimal oligosaccharide sequence of β-glucan required for exceptional immunogenicity was a hepta- or octamer and that longer glucans are not necessarily better antigens, a finding that may be of general importance. Most importantly, the octa-β-glucan-KLH conjugate provoked protective immunity against Candida albicans infection in a systemic challenge model in mice, suggesting the great potential of this glycoconjugate as a clinically useful immunoprophylactic antifungal vaccine.
authors: †Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States.
authors: Guochao
authors: G
authors: Liao
authors: †Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States.
authors: Zhifang
authors: Z
authors: Zhou
authors: †Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States.
authors: Srinivas
authors: S
authors: Burgula
authors: †Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States.|‡School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
authors: Jun
authors: J
authors: Liao
authors: §Department of Pharmacy, Shanghai East Hospital, Tongji University, 150 Jimo Road, Shanghai 200120, China.
authors: Cheng
authors: C
authors: Yuan
authors: ‡School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
authors: Qiuye
authors: Q
authors: Wu
authors: †Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States.
authors: Zhongwu
authors: Z
authors: Guo
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000276:immunology; D000946:Antigens, Fungal / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology; D002176:Candida albicans / Q000187:drug effects / Q000276:immunology; D002177:Candidiasis / Q000188:drug therapy / Q000276:immunology; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D005657:Fungal Vaccines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009844:Oligosaccharides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000276:immunology; D047071:beta-Glucans / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000276:immunology
chemical_list: D000935:Antifungal Agents; D000946:Antigens, Fungal; D005657:Fungal Vaccines; D009844:Oligosaccharides; D047071:beta-Glucans