The Conformation of the Mannopyranosyl Phosphate Repeating Unit of the Capsular Polysaccharide of <i>Neisseria meningitidis</i> Serogroup A and Its Carba‐Mimetic

Calloni, Ilaria; Unione, Luca; Jiménez‐Osés, Gonzalo; Corzana, Francisco; Bino, Linda Del; Corrado, Alessio; Pitirollo, Olimpia; Colombo, Cinzia; Lay, Luigi; Adamo, Roberto; Jiménez‐Barbero, Jesús

doi:10.1002/ejoc.201801003

Cited by 19 publications

(14 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, only carbaMenA DP8 competed for binding of an anti-MenA functional mAb, indicating that 8 repeating units are required to provide an effective synthetic antigen. While in silico analysis of carbaMenA related monomers has shown similar conformations with the natural sugar 54 , studies with oligomers up to the dodecamer have indicated that these longer structures may adopt a different overall conformation than their natural counterparts 55 . The results presented here show that the carbaMenA can adequately mimic the natural polysaccharide.…”

Section: Discussionmentioning

confidence: 99%

A stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A

Enotarpi

Tontini²,

Balocchi³

et al. 2020

Nat Commun

Self Cite

View full text Add to dashboard Cite

Neisseria meningitidis serogroup A capsular polysaccharide (MenA CPS) consists of (1 → 6)-2-acetamido-2-deoxy-α-D-mannopyranosyl phosphate repeating units, O-acetylated at position C3 or C4. Glycomimetics appear attractive to overcome the CPS intrinsic lability in physiological media, due to cleavage of the phosphodiester bridge, and to develop a stable vaccine with longer shelf life in liquid formulation. Here, we generate a series of non-acetylated carbaMenA oligomers which are proven more stable than the CPS. An octamer (DP8) inhibits the binding of a MenA specific bactericidal mAb and polyclonal serum to the CPS, and is selected for further in vivo testing. However, its CRM197 conjugate raises murine antibodies towards the non-acetylated CPS backbone, but not the natural acetylated form. Accordingly, random O-acetylation of the DP8 is performed, resulting in a structure (Ac-carbaMenA) showing improved inhibition of anti-MenA CPS antibody binding and, after conjugation to CRM197, eliciting anti-MenA protective murine antibodies, comparably to the vaccine benchmark.

show abstract

Section: Discussionmentioning

confidence: 99%

A stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A

Enotarpi

Tontini²,

Balocchi³

et al. 2020

Nat Commun

Self Cite

View full text Add to dashboard Cite

show abstract

“…The trimer 26 was able to induce specific anti‐MenA IgG antibodies with detectable bactericidal activity in vitro, suggesting that carba‐analogues can be used for the development of synthetic vaccines . Interestingly, the conformational behavior of these analogues was also investigated, showing that the carbasugar mimics preserved the 4 C 1 geometry of the corresponding natural fragments.…”

Section: Endocyclic Oxygen Replacementmentioning

confidence: 99%

Design and synthesis of glycomimetics: Recent advances

Tamburrini

Colombo

Bernardi

2019

Medicinal Research Reviews

Self Cite

View full text Add to dashboard Cite

In the past few decades, our understanding of glycan information‐encoding power has notably increased, thus leading to a significant growth also in the design and synthesis of glycomimetic probes. Combining data from multiple analytical sources, such as crystallography, nuclear magnetic resonance spectroscopy, and other biophysical methods (eg, surface plasmon resonance and carbohydrate microarrays) has allowed to shed light on the key interaction events between carbohydrates and their protein‐targets. However, the low metabolic stability of carbohydrates and their high hydrophilicity, which translates in low bioavailability, undermine their development as drugs. In this framework, the design of chemically modified analogues (called carbohydrate mimics or glycomimetics) appears as a valid alternative for the development of therapeutic agents. Glycomimetics, as structural and functional mimics of carbohydrates, can replace the native ligands in the interaction with target proteins, but are designed to show enhanced enzymatic stability and bioavailability and, possibly, an improved affinity and selectivity toward the target. In the present account, we specifically focus on the most recent advances in the design and synthesis of glycomimetics. In particular, we highlight the efforts of the scientific community in the development of straightforward synthetic procedures for the preparation of sugar mimics and in their preliminary biological evaluation.

show abstract

“…Ta ble 3g athers the results for the CPS Ia pentasaccharide 1.T he comparison reflectsagood agreement between the NMR-a nd the MD-derived distances for the glycosidicl inkages GlcNAcb1-3Gal and Glcb1-4Gal (defined by the interprotond istances H1GlcNAc-H3Gal and H1Glc-H4Gal, respectively). The F/Y population analysisf rom the MD simulation showedasingle population for F fulfillingt he exoanomeric effect (exo-syn-F), [29,30] and two populations around y for both linkages (Supporting Information, Figure S1).…”

Section: Conformational Analysismentioning

confidence: 99%

Regioselective Glycosylation Strategies for the Synthesis of Group Ia and Ib Streptococcus Related Glycans Enable Elucidating Unique Conformations of the Capsular Polysaccharides

Bino

Calloni

Oldrini

et al. 2019

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

Group B Streptococcus serotypes Ia and Ib capsular polysaccharides are key targets for vaccine development. In spite of their immunospecifity these polysaccharides share high structural similarity.B oth are composed of the same monosaccharide residues and differ only in the connection of the Neu5Aca2-3Gal side chain to the GlcNAc unit, which is a b1-4 linkage in serotype Ia and a b1-3 linkage in serotype Ib. The developmento fe fficient regioselective routes for GlcNAcb1-3[Glcb1-4]Gal synthons is described, which give access to different group B Streptococcus (GBS) Ia and Ib repeating unit frameshifts. These glycans were used to probe the conformation and molecular dynamics of the two polysaccharides, highlighting the different presentation of the protruding Neu5Aca2-3Gal moieties on the polysaccharide backbones and ah igherf lexibility of Ib polymer relative to Ia, which can impact epitope exposure.[b] Dr.I .C alloni, Dr.A .Ardµ,P rof. J.Supporting information (containingt he experimental procedures for the synthesis of oligosaccharides 1-5 and their characterization, molecular dynamicss imulations, and NMR spectra)and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.

show abstract

The Conformation of the Mannopyranosyl Phosphate Repeating Unit of the Capsular Polysaccharide of Neisseria meningitidis Serogroup A and Its Carba‐Mimetic

Cited by 19 publications

References 31 publications

A stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A

A stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A

Design and synthesis of glycomimetics: Recent advances

Regioselective Glycosylation Strategies for the Synthesis of Group Ia and Ib Streptococcus Related Glycans Enable Elucidating Unique Conformations of the Capsular Polysaccharides

Contact Info

Product

Resources

About