Synthesis of Mannosidase-Stable Man₃ and Man₄ Glycans Containing S-linked Manα1→2Man Termini

Abstract

Oligomannose glycans are of interest as HIV vaccine components, but they are subject to mannosidase degradation in vivo. Herein, we report the synthesis of oligosaccharides containing a thio linkage at the nonreducing end. A thio-linked dimannose donor participates in highly stereoselective glycosylations to afford trimannose and tetramannose fragments. Saturation transfer difference nuclear magnetic resonance (STD NMR) studies show that these glycans are recognized by HIV antibody 2G12, and we confirm that the reducing terminal S-linkage confers complete stability against x. manihotis mannosidase.

Synthesis and Immunological Evaluation of Pentamannose-Based HIV-1 Vaccine Candidates

“…To enhance its immunogenicity, three Man 5 derivatives including trifluoro-modified ( 2 ), monofluoro-modified ( 3 ), and S -linked ( 4 ) analogues were also synthesized (Figure ). Fluorination is a widely-used bioisosteric modification in the field of carbohydrate-based vaccine development since the rarity of fluorinated compounds in most organisms could improve the immunogenicity of fluorinated glycans meanwhile preserving the cross-reactivity of the induced immune responses. − The S -linked glycomimetics were also proved to have stronger immune efficacy previously, and the S -glycosidic bond is more stable under serum enzymatic hydrolysis. − Evidence has proved that mannosidase trimming degrades the terminal mannose motif in Man 9 GlcNAc 2 -based HIV-1 vaccines during in vivo tests. ,, Man 5 and its three analogues were coupled with the carrier protein cross-reacting material 197 (CRM197), and the immunological properties of the resulting glycoconjugates were evaluated in mice.…”

“…57−61 Evidence has proved that mannosidase trimming degrades the terminal mannose motif in Man 9 GlcNAc 2 -based HIV-1 vaccines during in vivo tests. 52,62,63 Man 5 and its three analogues were coupled with the carrier protein cross-reacting material 197 (CRM197), and the immunological properties of the resulting glycoconjugates were evaluated in mice.…”