Synthetic carbohydrate-based vaccines: challenges and opportunities

Ravinder, M.; Chen, Chiang-Yun; Wu, Chung‐Yi

doi:10.1186/s12929-019-0591-0

Cited by 125 publications

(86 citation statements)

References 168 publications

(157 reference statements)

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“…As study case we focus on carbohydrates, a class of molecules for which the stereochemistry and the high degree of functionalization are key reactivity factors. Carbohydrate chemistry is essential for accessing complex glycans that are used as tool compounds to investigate fundamental biological processes such as protein glycosylation 27 – 29 , as well as for the preparation of synthetic vaccines 30 – 32 . Predicting the outcome of carbohydrate transformations, such as regioselective protection/deprotection of multiple hydroxyl groups or the stereospecificity of glycosylation reactions, is a very difficult task even for experienced carbohydrate chemists 33 , 34 , implying that this field of research might particularly benefit from computer-assisted reaction prediction tools.…”

Section: Introductionmentioning

confidence: 99%

Transfer learning enables the molecular transformer to predict regio- and stereoselective reactions on carbohydrates

et al. 2020

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Organic synthesis methodology enables the synthesis of complex molecules and materials used in all fields of science and technology and represents a vast body of accumulated knowledge optimally suited for deep learning. While most organic reactions involve distinct functional groups and can readily be learned by deep learning models and chemists alike, regio- and stereoselective transformations are more challenging because their outcome also depends on functional group surroundings. Here, we challenge the Molecular Transformer model to predict reactions on carbohydrates where regio- and stereoselectivity are notoriously difficult to predict. We show that transfer learning of the general patent reaction model with a small set of carbohydrate reactions produces a specialized model returning predictions for carbohydrate reactions with remarkable accuracy. We validate these predictions experimentally with the synthesis of a lipid-linked oligosaccharide involving regioselective protections and stereoselective glycosylations. The transfer learning approach should be applicable to any reaction class of interest.

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Section: Introductionmentioning

confidence: 99%

Transfer learning enables the molecular transformer to predict regio- and stereoselective reactions on carbohydrates

et al. 2020

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“…This event leads to long-term immunological memory and production of high-affinity antibodies to prevent bacterial infection. Conjugated carbohydrate vaccines have proven effective against the infectious diseases caused by antibiotic-resistant bacteria [ 4 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Constructing conjugate vaccine against Salmonella Typhimurium using lipid-A free lipopolysaccharide

et al. 2020

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Background: Salmonella enterica serotype Typhimurium is a nontyphoidal and common foodborne pathogen that causes serious threat to humans. There is no licensed vaccine to prevent the nontyphoid bacterial infection caused by S. Typhimurium. Methods: To develop conjugate vaccines, the bacterial lipid-A free lipopolysaccharide (LFPS) is prepared as the immunogen and used to synthesize the LFPS-linker-protein conjugates 6a-9b. The designed bifunctional linkers 1-5 comprising either an o-phenylenediamine or amine moiety are specifically attached to the exposed 3-deoxy-Dmanno-octulosonic acid (Kdo), an α-ketoacid saccharide of LFPS, via condensation reaction or decarboxylative amidation. In addition to bovine serum albumin and ovalbumin, the S. Typhimurium flagellin (FliC) is also used as a self-adjuvanting protein carrier. Results: The synthesized conjugate vaccines are characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and fast performance liquid chromatography (FPLC), and their contents of polysaccharides and protein are determined by phenol-sulfuric acid assay and bicinchoninic acid assay, respectively. Enzyme-linked immunosorbent assay (ELISA) shows that immunization of mouse with the LFPS-linker-protein vaccines at a dosage of 2.5 μg is sufficient to elicit serum immunoglobulin G (IgG) specific to S. Typhimurium lipopolysaccharide (LPS). The straight-chain amide linkers in conjugates 7a-9b do not interfere with the desired immune response. Vaccines 7a and 7b derived from either unfractionated LFPS or the high-mass portion show equal efficacy in induction of IgG antibodies. The challenge experiments are performed by oral gavage of S. Typhimurium pathogen, and vaccine 7c having FliC as the self-adjuvanting protein carrier exhibits a high vaccine efficacy of 74% with 80% mice survival rate at day 28 post the pathogen challenge.

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“…Much effort is currently devoted to the generation of synthetic carbohydrate vaccines, in which chemically made oligosaccharides are used as antigens in conjugate vaccines 23 , 24 . The use of synthetic material has many advantages, including well-defined size, minimal (if any) batch-to-batch variation, and controlled conjugation chemistry.…”

Section: Introductionmentioning

confidence: 99%

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

Enotarpi

Tontini²,

Balocchi³

et al. 2020

Nat Commun

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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.

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Synthetic carbohydrate-based vaccines: challenges and opportunities

Cited by 125 publications

References 168 publications

Transfer learning enables the molecular transformer to predict regio- and stereoselective reactions on carbohydrates

Transfer learning enables the molecular transformer to predict regio- and stereoselective reactions on carbohydrates

Constructing conjugate vaccine against Salmonella Typhimurium using lipid-A free lipopolysaccharide

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

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