title: STD NMR study of the interactions between antibody 2G12 and synthetic oligomannosides that mimic selected branches of gp120 glycans.
abstract: The human immunodeficiency virus type-1 (HIV-1) is able to shield immunogenic peptide epitopes on its envelope spike (a trimer of two glycoproteins, gp120 and gp41) by presenting numerous host-derived N-linked glycans. Nevertheless, broadly neutralizing antibodies against gp120 and gp41 have been isolated from HIV-1-infected patients and provide protection against viral challenge in animal models. Among these, the monoclonal antibody 2G12 binds to clusters of high-mannose-type glycans that are present on the surface of gp120. These types of glycans have thus been envisaged as target structures for the development of synthetic agents capable of eliciting 2G12-like antibodies. High-resolution structural studies of 2G12 and chemically defined glycan-type ligands, including crystallographic data, have been performed to gain an insight into this interaction. Further studies are still required to design a carbohydrate-based vaccine for HIV. Our previous NMR studies highlighted different recognition modes of two branched synthetic oligosaccharides, a penta- and a heptamannoside, by 2G12 in solution. In order to clarify the underlying structural reasons for such different behaviors, we have herein "dissected" the branches into the linear tri- and tetra- oligomannosides by chemical synthesis and studied their interactions with 2G12 in solution by saturation transfer difference (STD) NMR spectroscopy. The results confirm the distinct preferences of 2G12 for the studied branches and afford explanations for the observed differences. This study provides important structural information for further ligand optimizations. Possible effects of structural modifications on the solvent-exposed end of the ligands are also discussed.
authors.affiliation: Laboratory of GlycoNanotechnology, Biofunctional Nanomaterial Unit, CIC biomaGUNE, Paseo de Miramón 182,20009 San Sebastián, Spain.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Enríquez-Navas
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Chiodo
authors.forename: Marco
authors.initials: M
authors.lastname: Marradi
authors.forename: Jesús
authors.initials: J
authors.lastname: Angulo
authors.forename: Soledad
authors.initials: S
authors.lastname: Penadés
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D046228:Microarray Analysis; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D011134:Polysaccharides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015699:HIV Envelope Protein gp120; D009844:Oligosaccharides; D011134:Polysaccharides; C514793:gp120 protein, Human immunodeficiency virus 1; C028569:oligomannoside