Pseudomonas aeruginosa is an opportunistic pathogen responsible for severe nosocomial infections.This multidrug-resistant bacterium can cause pneumonia and cystic fibrosis,both of which are associated with high morbid...Pseudomonas aeruginosa is an opportunistic pathogen responsible for severe nosocomial infections.This multidrug-resistant bacterium can cause pneumonia and cystic fibrosis,both of which are associated with high morbidity and mortality rates.The lipopolysaccharide of P.aeruginosa serves as an attractive target for the development of effective glycoconjugate vaccines.In this article,we report the first chemical synthesis of the highly challenging tetrasaccharide repeating unit of the P.aeruginosa serotype O3 O-antigen using a two-directional[1+(2+1)]glycosylation strategy.The synthesis is particularly challenging due to the poor nucleophilicity of the axial C4 hydroxyl group of l-galactose and the steric hindrance imposed by the 3S-hydroxybutyryl(Hb)chain.Furthermore,the presence of an acetyl group at the ortho position relative to the glycosylation site on l-galactose can lead to undesirable acetyl migration.Additionally,it is noteworthy that the selective removal of a 2-naphthylmethyl ether(Nap)during the late stages of synthesis,particularly in the presence of multiple benzyl groups,can be somewhat challenging to predict.Through the careful selection of synthetic strategies,building blocks,and optimized reaction conditions,we achieved the stereoselective glycosylations,selective oxidation of primary alcohols,remarkable enhancement of acceptor activity,and efficient introduction of the 3S-Hb group.The synthetic methodology presented in this work serves as a valuable reference for the preparation of structurally related oligosaccharides.By incorporating an aminopropyl linker,the target tetrasaccharide facilitates glycan microarray preparation and in vivo immunological assessments,thereby accelerating progress toward a synthetic glycoconjugate vaccine for P.aeruginosa.展开更多
The gut pathogen Enterocloster bolteae(E.bolteae)has been associated with autism spectrum disorder(ASD).The development of an E.bolteae vaccine to prevent gastrointestinal diseases,might be beneficial for understandin...The gut pathogen Enterocloster bolteae(E.bolteae)has been associated with autism spectrum disorder(ASD).The development of an E.bolteae vaccine to prevent gastrointestinal diseases,might be beneficial for understanding and treating ASD.Capsular polysaccharide(CPS)is a major virulence factor for E.bolteae.Based on an antigenicity evaluation of oligosaccharides associated with E.bolteae CPS and a structural revision of this carbohydrate antigen,two series of glycans including the D-Manp-D-Rhap type oligosaccharides 13-18 and the D-Ribp-D-Rhap type disaccharides 19-23 related to E.bolteae WAL-16351 CPS were prepared.The hydrogen-bond mediated glycosylation and conformational locking strategy facilitated the constructions of two 1,2-cis-β-glycosidic linkages.Glycan microarray analysis revealed that oligosaccharides 4,5,and 19 are recognized by antibodies in the anti-E.bolteae sera.The sera IgG antibodies induced by glycoconjugate 19-CRM197 recognize the CPS and bacteria specifically,whereas the IgG antibodies induced respectively by glycoconjugates 4-CRM197 and 5-CRM197 showed almost no binding to the CPS and bacteria.These results indicated that disaccharide 19 is a potential candidate for the development of E.bolteae vaccines.展开更多
An effective vaccine for human immunodeficiency virus(HIV) is urgently needed to prevent HIV infection and progression to acquired immune deficiency syndrome(AIDS). As glycosylation of viral proteins becomes better un...An effective vaccine for human immunodeficiency virus(HIV) is urgently needed to prevent HIV infection and progression to acquired immune deficiency syndrome(AIDS). As glycosylation of viral proteins becomes better understood, carbohydrate-based antiviral vaccines against special viruses have attracted much attention. Significant efforts in carbohydrate synthesis and immunogenicity research have resulted in the development of multiple carbohydrate-based HIV vaccines. This review summarizes recent advances in synthetic carbohydrate-based vaccines design strategies and the applications of these vaccines in the prevention of HIV.展开更多
Pseudomonas aeruginosa is an opportunistic pathogen responsible for cystic fibrosis,bloodstream infections and hospital-acquired pneumonia.The O-antigen of lipopolysaccharide on the cell surface of P.aeruginosa has be...Pseudomonas aeruginosa is an opportunistic pathogen responsible for cystic fibrosis,bloodstream infections and hospital-acquired pneumonia.The O-antigen of lipopolysaccharide on the cell surface of P.aeruginosa has been identified as a promising target for the development of carbohydrate-based vaccines.In this study,we present the first total synthesis of the tetrasaccharide repeating unit of P.aeruginosa serotype 4 O-antigen using a linear[((1+1)+1)+1]glycosylation strategy.All rare amino sugars were synthesized from commercially available monosaccharides.The formation of 1,2-cis L-fucosamine glycosidic bonds was achieved with high efficiency and stereoselectivity by judicious choice of C3/C4-OH protecting groups of L-fucosamine.The N-phenyl trifluoroacetimidate glycosyl donors have proven to be more efficient than selenoglycoside or thioglycoside donors during glycosylation,particularly when coupling with the low-reactivity C3-OH group of the O4-Bz protected L-FucN3 acceptor.TBSOTf has demonstrated higher efficacy as a catalyst compared to TMSOTf for promoting glycosylation with less reactive acceptors.The synthetic tetrasaccharide repeating unit of P.aeruginosa serotype 4 O-antigen,which incorporates a pentyl amine linker at the reducing end,has been prepared for conjugation with carrier proteins or for utilization in microarray studies aimed at further immunological investigations.展开更多
The eradication of Pseudomonas aeruginosa infections is becoming increasingly complex due to the emergence of multidrug-resistant strains,underscoring the urgent need for novel therapeutic strategies.Currently,no vacc...The eradication of Pseudomonas aeruginosa infections is becoming increasingly complex due to the emergence of multidrug-resistant strains,underscoring the urgent need for novel therapeutic strategies.Currently,no vaccine is available to prevent P.aeruginosa infections and the development of glycoconjugate vaccines based on P.aeruginosa lipopolysaccharides(LPS)presents significant challenges.To explore the immunological activity of the serotype O17 O-antigen,we present the first chemical synthesis of two hexasaccharides derived from the O17 O-antigen of P.aeruginosa,which possess distinct sequences.The synthesis of these two target hexasaccharides was accomplished using a chemoselective one-pot[2+2+2]assembly strategy and a common step-wise synthesis,respectively.The formation of β-mannosamine glycosidic linkages in products 1 and 2,was achieved through a direct stereoselective 1,2-cis-glycosylation involving 4,6-O-benzylidene-induced conformational locking facilitated by Ph_(2)SO/Tf_(2)O pre-activation,and an indirect 1,2-trans-β-glycosylation alongside SN2 substitution of azide groups at C2,respectively.The efficient synthesis of these conjugation-ready oligosaccharides from the O-antigen of P.aeruginosa serotype O17 will provide foundational materials for identifying key antigens and developing glycoconjugate vaccines.展开更多
Helicobacter pylori(H.pylori)infection is a threat to human health.The lipopolysaccharide(LPS)O-antigen holds promise for developing vaccines.It is meaningful to explore the immunological activity of oligosaccharides ...Helicobacter pylori(H.pylori)infection is a threat to human health.The lipopolysaccharide(LPS)O-antigen holds promise for developing vaccines.It is meaningful to explore the immunological activity of oligosaccharides with different lengths and frameshifts for antigen development.Herein,a glycan library of H.pylori O2 O-antigen containing eight fragments is constructed.After screening with anti-H.pylori O2 LPS sera and patients’sera by glycan microarray,the disaccharide HPO2G-2b and trisaccharide HPO2G-3a show strong antigenicity and then are separately conjugated with carrier protein CRM197.Both glycoconjugates elicit a robust immunoglobulin G(IgG)immune response in rabbits.The anti-HPO2G-3a IgG antibodies possess a much stronger binding affinity with the LPS and bacteria of H.pylori O2 than the anti-HPO2G-2b IgG antibodies.There is no cross-reaction between both sera IgG antibodies with LPS and bacteria of H.pylori O1,O6,and E.coli.The results demonstrate the trisaccharide HPO2G-3a is a promising candidate for H.pylori vaccine development.展开更多
Treponema is a Gram-negative anaerobic bacterium,among which the pathogenic Treponema can cause various diseases,such as venereal syphilis(Treponema pallidum),yaws(Treponema carateum),and oral diseases(Treponema denti...Treponema is a Gram-negative anaerobic bacterium,among which the pathogenic Treponema can cause various diseases,such as venereal syphilis(Treponema pallidum),yaws(Treponema carateum),and oral diseases(Treponema denticola and Treponema medium).Although different from conventional lipopolysaccharides,the extracellular glycoconjugate of Treponema may still be a potential antigen and provide a candidate for vaccine development.Hence,we completed the first chemical synthesis of Treponema medium ATCC 700293 tetrasaccharide precursor containing L-ornithine(L-Orn)and D-aspartic acid(D-Asp)derivatives.The efficiency of non-reducing end disaccharide formation has been improved by optimizing the assembly of the protecting groups in the donors and acceptors.Our[3+1]glycosylation strategy attempted to reduce the length of the acceptor to increase the nucleophilicity of the hydroxyl group,thereby improving the efficiency of synthesizing the target tetrasaccharide.The L-Orn derivative was introduced at the final stage due to its influence on the glycosylation stereospecificity and efficiency.Therefore,the successful introduction of two amino acid derivatives and the synthesis of a tetrasaccharide precursor with complex functional-group modifications have provided valuable insights for synthesizing other complex bacterial glycans.展开更多
基金the National Key R&D Program of China(No.2023YFC2308000)the National Natural Science Foundation of China(Nos.22478153,22477046,22177041)+2 种基金the Max Planck Society International Partner Group Programthe China Scholarship Council(CSC)the Fundamental Research Funds for the Central Universities for funding.
文摘Pseudomonas aeruginosa is an opportunistic pathogen responsible for severe nosocomial infections.This multidrug-resistant bacterium can cause pneumonia and cystic fibrosis,both of which are associated with high morbidity and mortality rates.The lipopolysaccharide of P.aeruginosa serves as an attractive target for the development of effective glycoconjugate vaccines.In this article,we report the first chemical synthesis of the highly challenging tetrasaccharide repeating unit of the P.aeruginosa serotype O3 O-antigen using a two-directional[1+(2+1)]glycosylation strategy.The synthesis is particularly challenging due to the poor nucleophilicity of the axial C4 hydroxyl group of l-galactose and the steric hindrance imposed by the 3S-hydroxybutyryl(Hb)chain.Furthermore,the presence of an acetyl group at the ortho position relative to the glycosylation site on l-galactose can lead to undesirable acetyl migration.Additionally,it is noteworthy that the selective removal of a 2-naphthylmethyl ether(Nap)during the late stages of synthesis,particularly in the presence of multiple benzyl groups,can be somewhat challenging to predict.Through the careful selection of synthetic strategies,building blocks,and optimized reaction conditions,we achieved the stereoselective glycosylations,selective oxidation of primary alcohols,remarkable enhancement of acceptor activity,and efficient introduction of the 3S-Hb group.The synthetic methodology presented in this work serves as a valuable reference for the preparation of structurally related oligosaccharides.By incorporating an aminopropyl linker,the target tetrasaccharide facilitates glycan microarray preparation and in vivo immunological assessments,thereby accelerating progress toward a synthetic glycoconjugate vaccine for P.aeruginosa.
基金the National Natural Science Foundation of China(Nos.22325803,22277042,22177041,22207042,22107037)the Max Planck Society International Partner Group Program,the China Scholarship Council(CSC)the Fundamental Research Funds for the Central Universities for funding。
文摘The gut pathogen Enterocloster bolteae(E.bolteae)has been associated with autism spectrum disorder(ASD).The development of an E.bolteae vaccine to prevent gastrointestinal diseases,might be beneficial for understanding and treating ASD.Capsular polysaccharide(CPS)is a major virulence factor for E.bolteae.Based on an antigenicity evaluation of oligosaccharides associated with E.bolteae CPS and a structural revision of this carbohydrate antigen,two series of glycans including the D-Manp-D-Rhap type oligosaccharides 13-18 and the D-Ribp-D-Rhap type disaccharides 19-23 related to E.bolteae WAL-16351 CPS were prepared.The hydrogen-bond mediated glycosylation and conformational locking strategy facilitated the constructions of two 1,2-cis-β-glycosidic linkages.Glycan microarray analysis revealed that oligosaccharides 4,5,and 19 are recognized by antibodies in the anti-E.bolteae sera.The sera IgG antibodies induced by glycoconjugate 19-CRM197 recognize the CPS and bacteria specifically,whereas the IgG antibodies induced respectively by glycoconjugates 4-CRM197 and 5-CRM197 showed almost no binding to the CPS and bacteria.These results indicated that disaccharide 19 is a potential candidate for the development of E.bolteae vaccines.
基金the National Science Foundation for Young Scientists of China(No.21302068)the Natural Science Foundation of Jiangsu Province,China(No.BK20130127,BK20140154,and BK20150140)+1 种基金the Public Health Research Center at Jiangnan University(No.JUPH201502)Key Laboratory of Carbohydrate Chemistry and Biotechnology Ministry of Education,Jiangnan University(KLCCB-KF201504)
文摘An effective vaccine for human immunodeficiency virus(HIV) is urgently needed to prevent HIV infection and progression to acquired immune deficiency syndrome(AIDS). As glycosylation of viral proteins becomes better understood, carbohydrate-based antiviral vaccines against special viruses have attracted much attention. Significant efforts in carbohydrate synthesis and immunogenicity research have resulted in the development of multiple carbohydrate-based HIV vaccines. This review summarizes recent advances in synthetic carbohydrate-based vaccines design strategies and the applications of these vaccines in the prevention of HIV.
基金funded by the National Natural Science Foundation of China(22207042,22277042,22325803)the National Key R&D Program of China(2023YFC2308000)the Open Project of Key Laboratory of Carbohydrate Chemistry and Biotechnology(Jiangnan University),Ministry of Education(KLCCBKF202203).
文摘Pseudomonas aeruginosa is an opportunistic pathogen responsible for cystic fibrosis,bloodstream infections and hospital-acquired pneumonia.The O-antigen of lipopolysaccharide on the cell surface of P.aeruginosa has been identified as a promising target for the development of carbohydrate-based vaccines.In this study,we present the first total synthesis of the tetrasaccharide repeating unit of P.aeruginosa serotype 4 O-antigen using a linear[((1+1)+1)+1]glycosylation strategy.All rare amino sugars were synthesized from commercially available monosaccharides.The formation of 1,2-cis L-fucosamine glycosidic bonds was achieved with high efficiency and stereoselectivity by judicious choice of C3/C4-OH protecting groups of L-fucosamine.The N-phenyl trifluoroacetimidate glycosyl donors have proven to be more efficient than selenoglycoside or thioglycoside donors during glycosylation,particularly when coupling with the low-reactivity C3-OH group of the O4-Bz protected L-FucN3 acceptor.TBSOTf has demonstrated higher efficacy as a catalyst compared to TMSOTf for promoting glycosylation with less reactive acceptors.The synthetic tetrasaccharide repeating unit of P.aeruginosa serotype 4 O-antigen,which incorporates a pentyl amine linker at the reducing end,has been prepared for conjugation with carrier proteins or for utilization in microarray studies aimed at further immunological investigations.
基金funded by the National Natural Science Foundation of China(22277042,22107037,22325803)the National Key R&D Program of China(2023YFC2308000)the Open Project of Key Laboratory of Carbohydrate Chemistry and Biotechnology(Jiangnan University),Ministry of Education(KLCCBKF202202).
文摘The eradication of Pseudomonas aeruginosa infections is becoming increasingly complex due to the emergence of multidrug-resistant strains,underscoring the urgent need for novel therapeutic strategies.Currently,no vaccine is available to prevent P.aeruginosa infections and the development of glycoconjugate vaccines based on P.aeruginosa lipopolysaccharides(LPS)presents significant challenges.To explore the immunological activity of the serotype O17 O-antigen,we present the first chemical synthesis of two hexasaccharides derived from the O17 O-antigen of P.aeruginosa,which possess distinct sequences.The synthesis of these two target hexasaccharides was accomplished using a chemoselective one-pot[2+2+2]assembly strategy and a common step-wise synthesis,respectively.The formation of β-mannosamine glycosidic linkages in products 1 and 2,was achieved through a direct stereoselective 1,2-cis-glycosylation involving 4,6-O-benzylidene-induced conformational locking facilitated by Ph_(2)SO/Tf_(2)O pre-activation,and an indirect 1,2-trans-β-glycosylation alongside SN2 substitution of azide groups at C2,respectively.The efficient synthesis of these conjugation-ready oligosaccharides from the O-antigen of P.aeruginosa serotype O17 will provide foundational materials for identifying key antigens and developing glycoconjugate vaccines.
基金financial support from the National Natural Science Foundation of China(22177041,22277042,22077052,22107037,22207042)the China Postdoctoral Science Foundation(2021M691279)+1 种基金the 111 Project(111-2-06)the Max Planck Society International Partner Group Program,and the China Scholarship Council(CSC)for funding.P.H.S.thanks the Max Plank Society forgenerous financial support.
文摘Helicobacter pylori(H.pylori)infection is a threat to human health.The lipopolysaccharide(LPS)O-antigen holds promise for developing vaccines.It is meaningful to explore the immunological activity of oligosaccharides with different lengths and frameshifts for antigen development.Herein,a glycan library of H.pylori O2 O-antigen containing eight fragments is constructed.After screening with anti-H.pylori O2 LPS sera and patients’sera by glycan microarray,the disaccharide HPO2G-2b and trisaccharide HPO2G-3a show strong antigenicity and then are separately conjugated with carrier protein CRM197.Both glycoconjugates elicit a robust immunoglobulin G(IgG)immune response in rabbits.The anti-HPO2G-3a IgG antibodies possess a much stronger binding affinity with the LPS and bacteria of H.pylori O2 than the anti-HPO2G-2b IgG antibodies.There is no cross-reaction between both sera IgG antibodies with LPS and bacteria of H.pylori O1,O6,and E.coli.The results demonstrate the trisaccharide HPO2G-3a is a promising candidate for H.pylori vaccine development.
基金the National Natural Science Foundation of China(22325803,22077052,22277042,22107037,22177041,22207042)the China Postdoctoral Science Foundation(2021M691279)the National Key R&D Program of China(2023YFC2308000).
文摘Treponema is a Gram-negative anaerobic bacterium,among which the pathogenic Treponema can cause various diseases,such as venereal syphilis(Treponema pallidum),yaws(Treponema carateum),and oral diseases(Treponema denticola and Treponema medium).Although different from conventional lipopolysaccharides,the extracellular glycoconjugate of Treponema may still be a potential antigen and provide a candidate for vaccine development.Hence,we completed the first chemical synthesis of Treponema medium ATCC 700293 tetrasaccharide precursor containing L-ornithine(L-Orn)and D-aspartic acid(D-Asp)derivatives.The efficiency of non-reducing end disaccharide formation has been improved by optimizing the assembly of the protecting groups in the donors and acceptors.Our[3+1]glycosylation strategy attempted to reduce the length of the acceptor to increase the nucleophilicity of the hydroxyl group,thereby improving the efficiency of synthesizing the target tetrasaccharide.The L-Orn derivative was introduced at the final stage due to its influence on the glycosylation stereospecificity and efficiency.Therefore,the successful introduction of two amino acid derivatives and the synthesis of a tetrasaccharide precursor with complex functional-group modifications have provided valuable insights for synthesizing other complex bacterial glycans.
