title: Synthesis of antifungal vaccines by conjugation of β-1,2 trimannosides with T-cell peptides and covalent anchoring of neoglycopeptide to tetanus toxoid.
abstract: Selective strategies for the construction of novel three component glycoconjugate vaccines presenting Candida albicans cell wall glycan (β-1,2 mannoside) and polypeptide fragments on a tetanus toxoid carrier are described. The first of two conjugation strategies employed peptides bearing an N-terminal thiopropionyl residue for conjugation to a trisaccharide equipped with an acrylate linker and a C-terminal S-acetyl thioglycolyl moiety for subsequent linking of neoglycopeptide to bromoacetylated tetanus toxoid. Michael addition of acrylate trisaccharides to peptide thiol under mildly basic conditions gave a mixture of N- and C- terminal glyco-peptide thioethers. An adaptation of this strategy coordinated S-acyl protection with anticipated thioester exchange equilibria. This furnished a single chemically defined fully synthetic neoglycopeptide conjugate that could be anchored to a tetanus toxoid carrier and avoids the introduction of exogenous antigenic groups. The second strategy retained the N-terminal thiopropionyl residue but replaced the C-terminal S-acetate functionality with an azido group that allowed efficient, selective formation of neoglycopeptide thioethers and subsequent conjugation of these with propargylated tetanus toxoid, but introduced potentially antigenic triazole linkages.
authors.affiliation: Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cartmell
authors.affiliation: Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Paszkiewicz
authors.affiliation: Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Dziadek
authors.affiliation: Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: Pui-Hang
authors.initials: PH
authors.lastname: Tam
authors.affiliation: Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: Thanh
authors.initials: T
authors.lastname: Luu
authors.affiliation: Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: Susmita
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Lipinski
authors.affiliation: Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada. Electronic address: dave.bundle@ualberta.ca.
authors.forename: David R
authors.initials: DR
authors.lastname: Bundle
mesh_terms: D000215:Acylation; D002176:Candida albicans / Q000276:immunology; D060326:Chemistry Techniques, Synthetic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005657:Fungal Vaccines / Q000138:chemical synthesis* / Q000737:chemistry*; D006020:Glycopeptides / Q000737:chemistry*; D008362:Mannosides / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013745:Tetanus Toxoid / Q000138:chemical synthesis* / Q000737:chemistry*; D014312:Trisaccharides / Q000737:chemistry; D018074:Vaccines, Conjugate / Q000737:chemistry
chemical_list: D018984:Epitopes, T-Lymphocyte; D005657:Fungal Vaccines; D006020:Glycopeptides; D008362:Mannosides; D013438:Sulfhydryl Compounds; D013745:Tetanus Toxoid; D014312:Trisaccharides; D018074:Vaccines, Conjugate
keywords: Glycoconjugate vaccine; Glycopeptide tetanus toxoid conjugate; Synthesis of glycopeptide; Thiol thioester exchange