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1.
ACS Infect Dis ; 6(8): 2181-2191, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32687317

RESUMO

Pneumolysin (Ply), pneumococcal surface protein A (PspA), and pneumococcal surface adhesin A (PsaA) are promising cell surface protein antigen targets for Streptococcus pneumoniae (Spn) vaccine development. Herein, we designed and recombined two fusion proteins, named YAPO and YAPL, which contained the main antigenic epitopes of Ply, PspA, and PsaA. In-depth immunological evaluations revealed that YAPO and YAPL had strong immunocompetence to be well-qualified potential carrier proteins. To verify this possibility, a serotype 3 Spn (ST3) CPS pentasaccharide was conjugated to each fusion protein to generate the resultant glycoconjugates. Immunological studies in mice revealed that, as compared with TT conjugate, YAPO and YAPL conjugates provoked robust T-cell dependent immune responses that could provide better recognition, in vitro efficient opsonophagocytosis, and in vivo effective protection against various serotypes of Spn. Collectively, YAPO and YAPL were identified as immunopotentiating carriers that could help convert immunologically inactive ST3 pentasaccharide into a T cell-dependent antigen and provide efficient and broad spectrum of immunoprotection coverage so as to formulate functional glycoconjugate vaccines against Spn infections.


Assuntos
Proteínas de Transporte , Infecções Pneumocócicas , Animais , Glicoconjugados , Camundongos , Camundongos Endogâmicos BALB C , Infecções Pneumocócicas/prevenção & controle , Proteínas Recombinantes de Fusão/genética
2.
ACS Infect Dis ; 5(8): 1423-1432, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31126171

RESUMO

Streptococcus pneumoniae serotype 3 (ST3) is one of the main pneumococcal strains that can cause severe invasive diseases, but its current vaccines are relatively inefficient. To develop more effective ST3 vaccines, tetanus toxoid (TT) conjugates of the synthetic penta-, hexa-, hepta-, and octasaccharide analogs of ST3 capsular polysaccharide (CPS) were systematically studied. These conjugates, especially those of penta- and hexasaccharides, were demonstrated to induce extremely robust T cell-dependent immune responses in mouse. Various studies also revealed that the induced antibodies could recognize ST3 CPS and mediate in vitro opsonophagocytic killing of ST3 cells. It was proved ultimately that immunization with the hexasaccharide-TT conjugate could completely protect mice from ST3-caused infection and lung damage and significantly elongate mouse survival. It was proposed that this conjugate functions through the help of CD4+ T cells and via promoting Th cell differentiation into carbohydrate antigen-specific Th2 cells to establish humoral immunity. In conclusion, ST3 CPS hexasaccharide-TT was identified as a particularly promising ST3 vaccine candidate worthy of further investigation and development.


Assuntos
Anticorpos Antibacterianos/sangue , Linfócitos T CD4-Positivos/imunologia , Glicoconjugados/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Estreptocócicas/imunologia , Streptococcus pneumoniae/imunologia , Animais , Feminino , Glicoconjugados/administração & dosagem , Glicoconjugados/química , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções Pneumocócicas/imunologia , Polissacarídeos Bacterianos/administração & dosagem , Polissacarídeos Bacterianos/química , Polissacarídeos Bacterianos/imunologia , Sorogrupo , Vacinas Estreptocócicas/administração & dosagem , Vacinas Estreptocócicas/síntese química , Toxoide Tetânico/imunologia , Células Th1/imunologia
3.
Org Biomol Chem ; 17(5): 1071-1075, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30648163

RESUMO

A new ß-rhamnoslytransferase Cps23FT from Streptococcus pneumonia serotype 23F was expressed and characterized. Its enzymatic activity and function were confirmed for the first time by utilizing enzymatically prepared dTDP-Rha and chemically synthesized Glcα-PP-(CH2)11-OPh as substrates. This reaction gave the desired disaccharide Rhaß-1,4-Glcα-PP-(CH2)11-OPh in a good isolated yield (67%), suggesting the potential of Cps23FT as a tool enzyme for the synthesis of complex oligosaccharides containing difficult ß-rhamnosyl linkages. Furthermore, site-directed mutagenesis of Cps23FT disclosed that its 271DKD273 motif was critical for the enzymatic activity and most likely the binding site for the required divalent metal cation.


Assuntos
Proteínas de Bactérias/metabolismo , Hexosiltransferases/metabolismo , Ramnose/metabolismo , Streptococcus pneumoniae/enzimologia , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Especificidade por Substrato
4.
Chemistry ; 24(32): 8205-8216, 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29528515

RESUMO

A highly convergent and efficient strategy was developed for the chemical synthesis of complex oligosaccharides of Streptococcus pneumoniae type 3 capsular polysaccharides that contain multiple glucuronic acid units. Once the oligoglucosides were efficiently and stereoselectively assembled, the designated glucose units were regioselectively oxidized to glucuronic acid in one step at the final synthetic stage, which helped avoid difficult glycosylations that involved glucuronic acid. The target oligosaccharides had a free amino group at the reducing terminus and varied caps at the non-reducing terminus to enable further modification and structure-activity relationship studies. Immunological evaluations of the oligosaccharide-tetanus toxoid conjugates showed that they elicited robust T-cell-dependent immunoglobulin G antibody responses and that the sugar chain length had a major impact on their immunological properties. In particular, the penta- and hexasaccharides were identified as promising antigens for vaccine development.


Assuntos
Cápsulas Bacterianas/química , Imunoglobulina G/imunologia , Oligossacarídeos/síntese química , Polissacarídeos Bacterianos/imunologia , Streptococcus pneumoniae/química , Toxoide Tetânico , Glicosilação , Oligossacarídeos/química , Polissacarídeos Bacterianos/química , Sorogrupo
5.
Carbohydr Res ; 451: 1-11, 2017 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-28917967

RESUMO

The trisaccharide repeating unit of an O-antigen derived from Burkholderia cenocepacia and its dimer, i.e., α-L-Rhap-(1 â†’ 3)-α-D-GalpNAc-(1 â†’ 3)-ß-D-GalpNAc-O(CH2)3N3 (1) and α-L-Rhap-(1 â†’ 3)-α-D-GalpNAc-(1 â†’ 3)-ß-D-GalpNAc-(1 â†’ 4)-α-L-Rhap-(1 â†’ 3)-α-D-GalpNAc-(1 â†’ 3)-ß-D-GalpNAc-O(CH2)3N3 (2), respectively, were synthesized via a highly convergent strategy. Glycosylation of galactosaminyl acceptor 4 with galactosaminyl trichloroacetimidate donor 5 was followed by condensation of resulting disaccharide acceptor 12 with rhamnosyl imidate donor 6 to furnish stereoselectively trisaccharyl thioglycoside 3, which was used as a key and common glycosyl donor for the construction of both 1 and 2. Title molecule 1 was prepared by glycosylation of 3-azidopropanol with 3 and subsequently global deprotection, whereas coupling reaction of 3 with a trisaccharide acceptor 21 containing an 2,3-O-position acetonide-modified rhamnose residue, followed by global deprotection, generated the dimer 2 in a convergent [3 + 3] manner.


Assuntos
Burkholderia cenocepacia/química , Antígenos O/química , Oligossacarídeos/química , Oligossacarídeos/síntese química , Trissacarídeos/química , Trissacarídeos/síntese química , Sequência de Carboidratos
6.
Org Lett ; 19(12): 3123-3126, 2017 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-28548838

RESUMO

Two structurally defined, functionalized glycans of lipoteichoic acid (LTA, also known as PS-III) from C. difficile, which have one or two repeating units of LTA linked to the core trisaccharide, were efficiently synthesized via a convergent [2 + 3] or [2 + 2 + 3] strategy. The α-linkage of both N-acetylglucosamine residues in the repeating unit were constructed with glycosyl imidates of azidosugars as donors, while the phosphodiester bridges between the oligosaccharides were fashioned using H-phosphonate chemistry. Both synthetic targets contained a 3-aminopropyl group at the core trisaccharide reducing end, facilitating their conjugation to other biomolecules to afford conjugates useful for various biological studies and applications.


Assuntos
Clostridioides difficile , Lipopolissacarídeos , Estrutura Molecular , Polissacarídeos , Ácidos Teicoicos
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