Multicomponent polysaccharide–protein bioconjugation in the development of antibacterial glycoconjugate vaccine candidates

Méndez, Yanira; Chang, Janoi; Humpierre, Ana R; Zanuy, Abel; Garrido, Raine; Vasco, Aldrin V.; Pedroso, Jessy; Santana, Darielys; Rodríguez, Laura; García-Rivera, Dagmar; Valdés, Yolanda; Vérez-Bencomo, Vicente; Rivera, Daniel G.

doi:10.1039/c7sc05467j

Cited by 45 publications

(39 citation statements)

References 66 publications

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“…Coupling high-resolution mass spectrometry and 1 H NMR techniques was tested with Neisseria meningitidis serogroup B, enabling simultaneous analysis of conjugation reaction course and final products (Yu et al 2018 ). However, the utilisation of mass spectrometry with polydisperse macromolecules (10–100 kDa), like S. Typhi O-PS, provides less information as in the case of glycoconjugates derived from synthetic antigens or less complex glycans (Méndez et al 2018 ).…”

Section: Part IIImentioning

confidence: 99%

Glycoconjugate vaccines against Salmonella enterica serovars and Shigella species: existing and emerging methods for their analysis

et al. 2021

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The global spread of enteric disease, the increasingly limited options for antimicrobial treatment and the need for effective eradication programs have resulted in an increased demand for glycoconjugate enteric vaccines, made with carbohydrate-based membrane components of the pathogen, and their precise characterisation. A set of physico-chemical and immunological tests are employed for complete vaccine characterisation and to ensure their consistency, potency, safety and stability, following the relevant World Health Organization and Pharmacopoeia guidelines. Variable requirements for analytical methods are linked to conjugate structure, carrier protein nature and size and O-acetyl content of polysaccharide. We investigated a key stability-indicating method which measures the percent free saccharide of Salmonella enterica subspecies enterica serovar Typhi capsular polysaccharide, by detergent precipitation, depolymerisation and HPAEC-PAD quantitation. Together with modern computational approaches, a more precise design of glycoconjugates is possible, allowing for improvements in solubility, structural conformation and stability, and immunogenicity of antigens, which may be applicable to a broad spectrum of vaccines. More validation experiments are required to establish the most effective and suitable methods for glycoconjugate analysis to bring uniformity to the existing protocols, although the need for product-specific approaches will apply, especially for the more complex vaccines. An overview of current and emerging analytical approaches for the characterisation of vaccines against Salmonella Typhi and Shigella species is described in this paper. This study should aid the development and licensing of new glycoconjugate vaccines aimed at the prevention of enteric diseases.

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Section: Part IIImentioning

confidence: 99%

Glycoconjugate vaccines against Salmonella enterica serovars and Shigella species: existing and emerging methods for their analysis

et al. 2021

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“…While the Ugi reactionh as been the objecto fe xtensive studies for the conjugation and stapling of peptides, only ah andful of publications report the use of proteins as coupling partners. [32][33][34][35][36] Most notably,a ll these strategies use the four-component version of the Ugi reaction (U-4CR); that is, they only target as ingle site at the protein surface, whether it be an amino acidr esidue (lysines or aspartates/ glutamates) or aldehydes from the glycanp ortion after periodate oxidation, and the approach necessitates the use of av ast excesso fr eagents (up to 4000 equivalents) and long reaction times (up to 4days). In addition, the absence of detailed analytical investigations precludes the conclusiont hat the Ugi reaction, and not an uncontrolled side reaction, wasi ndeed responsible for the bioconjugation.…”

Section: Introductionmentioning

confidence: 99%

“…A solution of hydroxylamine would then simply be added at the end of the reaction to regenerate the amino groups of these lysine residues that did not partake in the multicomponent reaction. While the Ugi reaction has been the object of extensive studies for the conjugation and stapling of peptides, only a handful of publications report the use of proteins as coupling partners [32–36] . Most notably, all these strategies use the four‐component version of the Ugi reaction (U‐4CR); that is, they only target a single site at the protein surface, whether it be an amino acid residue (lysines or aspartates/ glutamates) or aldehydes from the glycan portion after periodate oxidation, and the approach necessitates the use of a vast excess of reagents (up to 4000 equivalents) and long reaction times (up to 4 days).…”

Section: Introductionmentioning

confidence: 99%

Investigating Ugi/Passerini Multicomponent Reactions for the Site‐Selective Conjugation of Native Trastuzumab**

Sornay

Hessmann

Erb

et al. 2020

Chemistry A European J

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Site-selective modificationo fp roteins hasb een the object of intense studies over the past decades, especially in the therapeutic field. Prominent resultsh ave been obtained with recombinant proteins,f or which site-specific conjugation is made possible by the incorporation of particular aminoa cid residues or peptides equences. In parallel, methods for the site-selective and site-specific conjugation of native andn atural proteins are starting to thrive, allowing the controlled functionalization of various types of amino acid residues.P ursuingt he efforts in this field, we planned to develop an ew typeo fs ite-selective method, aiming at the simultaneous conjugation of two amino acid residues. We reasonedt hat this should give higher chances of developing as ite-selective strategy compared to the great majority of existing methods that solely target as ingle residue. We opted for the Ugi four-centre three-component reaction to implement this idea, with the aim of conjugating the sidechain amine and carboxylate groups of two neighbouring lysine and aspartate/glutamate. Herein,w es how that this strategyc an give access to valuable antibody conjugates bearings everald ifferent payloads;f urthermore, the approach limits the potential conjugation sites to only six on the model antibody trastuzumab.

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“…Unfortunately, although MCRs have been extensively used to 980 modify mono-and oligosaccharides 91 and conjugate poly-981 saccharides in solution-phase approaches [92][93][94][95][96][97] , MCR chemistry 982…”

Section: Resultsmentioning

confidence: 99%

On-resin multicomponent protocols for biopolymer assembly and derivatization

et al. 2021

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MCRs are versatile convergent procedures that incorporate 50 three or more reactants into a final product, with the consequent 51 generation of higher levels of molecular complexity and diversity 52 than other traditional organic reactions using a similar synthetic 53 effort [10][11][12][13] . They have been employed in almost all areas 54 of chemical synthesis [10][11][12][14][15][16] , but their applications in drug 55 discovery and development have unquestionable dominated the 56 interest of the chemical community 10,17,18 . MCRs are especially 57 well suited for the construction of heterocyclic-often medic-58 inally privileged-scaffolds, a task where they are comparable to 59 cycloaddition reactions in terms of scope and chemical effi-60 ciency. Indeed, solution-phase protocols are predominant in 61 both the development of new multicomponent processes and 62 the implementation of known MCRs to synthesize bioactive 63 molecules 10-18 . However, solid-phase synthesis also gained Q5 Q6

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Multicomponent polysaccharide–protein bioconjugation in the development of antibacterial glycoconjugate vaccine candidates

Abstract: A multicomponent reaction enables the one-pot assembly of immunogenic multivalent glycoconjugates.

Cited by 45 publications

References 66 publications

Glycoconjugate vaccines against Salmonella enterica serovars and Shigella species: existing and emerging methods for their analysis

Glycoconjugate vaccines against Salmonella enterica serovars and Shigella species: existing and emerging methods for their analysis

Investigating Ugi/Passerini Multicomponent Reactions for the Site‐Selective Conjugation of Native Trastuzumab**

On-resin multicomponent protocols for biopolymer assembly and derivatization

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