Novel template-assembled oligosaccharide clusters as epitope mimics for HIV-neutralizing antibody 2G12. Design, synthesis, and antibody binding study.
The synthesis of a new class of template-assembled oligomannose clusters as the mimics of the epitope of the HIV-neutralizing antibody 2G12 is described. The novel oligomannose clusters were successfully assembled on a cyclic decapeptide template using the Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides to alkynes by introducing four units of a synthetic D1 arm tetrasaccharide (Manalpha1,2Manalpha1,2Manalpha1,3Manalpha-) of high-mannose N-glycan on one face of the template and two T-helper epitope peptides on the other face of the template. Their binding to human antibody 2G12 was studied using surface plasmon resonance (SPR) technology. It was found that while the synthetic monomeric D1 arm oligosaccharide and its fluorinated derivative interacted with 2G12 only weakly, the corresponding template-assembled oligosaccharide clusters showed high affinity to antibody 2G12, indicating a clear clustering effect in 2G12 recognition. Interestingly, the fluorinated D1 arm cluster, in which the 6-OH of the terminal mannosyl residue was replaced with a fluorine atom, showed a distinct kinetic model in 2G12 binding as compared with the cluster of the natural D1 arm oligosaccharides. The oligosaccharide clusters with varied length of spacer demonstrated different affinity to 2G12, suggesting that an appropriate spatial orientation of the sugar chains in the cluster was crucial for high affinity binding to the antibody 2G12. It was also found that the introduction of two T-helper epitopes onto the template did not affect the structural integrity of the oligomannose cluster. The novel synthetic glycoconjugates represent a new type of immunogen that may be able to raise carbohydrate-specific neutralizing antibodies against HIV-1.
Wang
Jingsong
J
Institute of Human Virology, University of Maryland, 725 W. Lombard Street, Baltimore, MD 21201, USA.
Li
Hengguang
H
Zou
Guozhang
G
Wang
Lai-Xi
LX
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D002240:Carbohydrate Sequence; D002241:Carbohydrates / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D000939:Epitopes / Q000737:chemistry*; D015483:HIV Antibodies / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008358:Mannose / Q000737:chemistry; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D009844:Oligosaccharides / Q000737:chemistry*; D020349:Surface Plasmon Resonance
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D002241:Carbohydrates; D000939:Epitopes; D015483:HIV Antibodies; D009844:Oligosaccharides; D008358:Mannose