Synthesis of Monoglucosylated High-Mannose-Type Dodecasaccharide, a Putative Ligand for Molecular Chaperone, Calnexin, and Calreticurin

Matsuo, Ichiro; Wada, Megumi; Manabe, Shino; Yamaguchi, Yoshiki; Otake, Keisuke; Kato, Koichi; Ito, Yukishige

doi:10.1021/ja021288q

Cited by 133 publications

(53 citation statements)

References 18 publications

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“…The synthesis of high mannose-type oligosaccharides, Man 9 GlcNAc 2 and its analogues, has been extensively explored (11,(32)(33)(34)(35)(36)(37) by using a convergent approach that is generally more concise and efficient. The one-pot programmable relative reactivity value (RRV) assay (14) revealed that thioglycoside disaccharide building block 10 (RRV ϭ 790) is less reactive than compound 11 (RRV ϭ 3638), 15 (RRV ϭ 3137), and 18 (RRV ϭ 4398).…”

Section: Resultsmentioning

confidence: 99%

Dissection of the carbohydrate specificity of the broadly neutralizing anti-HIV-1 antibody 2G12

Calarese

Lee

Huang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

284

260

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Human antibody 2G12 neutralizes a broad range of HIV-1 isolates. Hence, molecular characterization of its epitope, which corresponds to a conserved cluster of oligomannoses on the viral envelope glycoprotein gp120, is a high priority in HIV vaccine design. A prior crystal structure of 2G12 in complex with Man 9GlcNAc2 highlighted the central importance of the D1 arm in antibody binding. To characterize the specificity of 2G12 more precisely, we performed solution-phase ELISA, carbohydrate microarray analysis, and cocrystallized Fab 2G12 with four different oligomannose derivatives (Man 4, Man5, Man7, and Man8) that compete with gp120 for binding to 2G12. Our combined studies reveal that 2G12 is capable of binding both the D1 and D3 arms of the Man 9GlcNAc2 moiety, which would provide more flexibility to make the required multivalent interactions between the antibody and the gp120 oligomannose cluster than thought previously. These results have important consequences for the design of immunogens to elicit 2G12-like neutralizing antibodies as a component of an HIV vaccine. 2G12 antibody ͉ HIV vaccine ͉ oligomannoses There is widespread agreement that the most promising approach to contain the ongoing HIV pandemic is through the development of an effective vaccine (1, 2). However, HIV vaccine design has faced many difficulties including, prominently, the lack of an immunogen able to elicit broadly neutralizing antibodies (Abs). The feasibility of developing such an immunogen is suggested by a small panel of broadly neutralizing human monoclonal antibodies (mAbs) that have been isolated from seropositive donors (3). One of these Abs, 2G12, recognizes a conserved and unusually dense cluster of oligomannose residues on the ''silent face'' of gp120, the major envelope protein of HIV-1 (4, 5). Many lectins have been identified that can bind to envelope and act antivirally, but 2G12 remains the only known anti-carbohydrate protein that has been specifically elicited to HIV-1 in an adaptive immune response (6). 2G12 has an unusual architecture in which the arms of the IgG swap variable heavy domains, creating a domainswapped dimer of Fabs (7). The crystal structure of Fab 2G12 complexed with Man 9 GlcNAc 2 indicated that the conventional Ab-binding sites are occupied by the D1 arms of the Man 9 GlcNAc 2 moieties (1; Fig. 1) (7). The terminal Man␣1-2Man residues of the D1 branch account for 85% of the Fab contacts to Man 9 GlcNAc 2 , although the disaccharide by itself is 50-fold less potent in binding to 2G12 than Man 9 GlcNAc 2 (7).Based on these structural results, several initiatives have been launched to design novel immunogens that will elicit 2G12-like Abs (8-12). Recently, we described the design and synthesis of novel antigens, oligomannoses 2-6 (Fig. 1), that bind to mAb 2G12 (13). The Man␣1-2Man-containing oligomannoses 4, 5, and 6 were identified as new epitope mimics that inhibit the binding of gp120 to mAb 2G12 as well as, or better than, Man 9 GlcNAc 2 (13). Encouraged by this result, we now report the desig...

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Section: Resultsmentioning

confidence: 99%

Dissection of the carbohydrate specificity of the broadly neutralizing anti-HIV-1 antibody 2G12

Calarese

Lee

Huang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

284

260

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“…Since the achievement of the total synthesis of high-man- nose-type glycans, [18][19][20] various substrates for UGGT1 have been developed taking advantage of fully chemical synthesis (Fig. 2).…”

Section: Non-proteinic Substratesmentioning

confidence: 99%

Chemical Approaches to Elucidate Enzymatic Profiles of UDP-Glucose: Glycoprotein Glucosyltransferase

Hachisu

Ito

2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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In the endoplasmic reticulum (ER), uridine 5′-diphosphate-glucose: glycoprotein glucosyltransferase 1 (UGGT1) recognizes misfolded glycoproteins and transfers a glucose residue to the specific non-reducing end of high-mannose-type glycans. However, precise molecular mechanism by which UGGT1 senses the folding has not been understood clearly. To address this issue, various model substrates for UGGT1 have been prepared using biological approaches. Recently, we introduced chemical approaches using synthetic glycan probes that were designed for studying N-glycan processing in the ER and Golgi apparatus. Our approach can outfit the homogeneous and functionalized glycan probes. In this review, recent results on functional analysis of UGGT1 are summarized.

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“…High-mannose-type glycans are known to interact with a variety of proteins, such as chaperones, lectins, glycosidases, glycosyltransferases, cargo-receptors, and ubiquitin ligases, playing critical roles in the "quality control" of glycoproteins. We have completed the synthesis of most of the high-mannose-type glycans that exist in the ER (13,14,15,16). Tetrahedron, 2006, 62, 8262), and these compounds are under current use as probes to investigate various protein-carbohydrate interactions in glycoprotein quality control (vide infra).…”

Section: A Prefacementioning

confidence: 99%

My Stroll in the Backyard of Carbohydrate Chemistry

Ito

2010

TIGG

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The fields of "Glycobiology" and "Glycotechnology" are gaining an increasing amount of attention. A major part of my research has been directed at the synthesis and functional analysis of glycoconjugate oligosaccharides of various origins. In this mini-review, I wish to summarize my research history in carbohydrate chemistry of the last 12 years. Representative subjects have been 1) synthetic studies on Asn-linked glycan chains, 2) synthesis of novel glycoprotein structures, 3) approaches to polymer-support synthesis of oligosaccharides, 4) development of new reactions for the synthesis of glycoprotein-related molecules, 5) studies on the synthesis of glycoproteins, 6) analyses of glycoprotein processing and protein quality control system, 7) synthesis of glycosyltransferase inhibitors, 8) synthesis of biologically active glycolipids, and 9) synthesis and biological activities on mycobacterial cell wall components.

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Synthesis of Monoglucosylated High-Mannose-Type Dodecasaccharide, a Putative Ligand for Molecular Chaperone, Calnexin, and Calreticurin

Cited by 133 publications

References 18 publications

Dissection of the carbohydrate specificity of the broadly neutralizing anti-HIV-1 antibody 2G12

Dissection of the carbohydrate specificity of the broadly neutralizing anti-HIV-1 antibody 2G12

Chemical Approaches to Elucidate Enzymatic Profiles of UDP-Glucose: Glycoprotein Glucosyltransferase

My Stroll in the Backyard of Carbohydrate Chemistry

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