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Pavol Kováč - One of the best experts on this subject based on the ideXlab platform.
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towards the complete synthetic o antigen of vibrio cholerae o1 serotype inaba improved synthesis of the conjugation ready upstream terminal Hexasaccharide determinant
RSC Advances, 2019Co-Authors: Mana Mohan Mukherjee, E D Stevens, Pavol KováčAbstract:Synthesis of the upstream terminal Hexasaccharide part of the lipopolysaccharides (LPS) of Vibrio cholerae O1, serotype Inaba has been improved. The key improvements include but are not limited to optimized conditions for the stereoselectivity of glycosylation reactions involved and fewer number of synthetic steps, compared to previous approaches. Particularly noteworthy is conducting the glycosylation of the very reactive glycosyl acceptor 8-azido-3,6-dioxaoctanol with the fully assembled Hexasaccharide trichloroacetimidate under thermodynamic control. It produced the desired α glycoside with an α : β ratio of 7 : 1, compared with the ratio of 1.1 : 1, observed when the coupling was conducted conventionally. Several substances, which were previously obtained in purity acceptable only for synthetic intermediates, were now obtained in the analytically pure state and were fully characterized. The structure of the key trisaccharide glycosyl acceptor was confirmed by single-crystal X-ray structure determination.
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Multimeric bivalent immunogens from recombinant tetanus toxin H_C fragment, synthetic Hexasaccharides, and a glycopeptide adjuvant
Glycoconjugate Journal, 2010Co-Authors: Aileen F. G. Bongat, Rina Saksena, Roberto Adamo, Yukari Fujimoto, Zenyu Shiokawa, Dwight C. Peterson, Koichi Fukase, Willie F. Vann, Pavol KováčAbstract:Using recombinant tetanus toxin H_C fragment (rTT-H_C) as carrier, we prepared multimeric bivalent immunogens featuring the synthetic Hexasaccharide fragment of O-PS of Vibrio cholerae O:1, serotype Ogawa, in combination with either the synthetic Hexasaccharide fragment of O-PS of Vibrio cholerae O:1, serotype Inaba, or a synthetic disaccharide tetrapeptide peptidoglycan fragment as adjuvant. The conjugation reaction was effected by squaric acid chemistry and monitored in virtually real time by SELDI-TOF MS. In this way, we could prepare well-defined immunogens with predictable carbohydrate–carrier ratio, whose molecular mass and the amount of each saccharide attached could be independently determined. The ability to prepare such neoglycoconjugates opens unprecedented possibilities for preparation of conjugate vaccines for bacterial diseases from synthetic carbohydrates.
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Length of the linker and the interval between immunizations influences the efficacy of Vibrio cholerae O1, Ogawa Hexasaccharide neoglycoconjugates.
FEMS Immunology & Medical Microbiology, 2006Co-Authors: Rina Saksena, Terri K. Wade, Pavol Kováč, William F. WadeAbstract:Ogawa Hexasaccharide neoglycoconjugates induce protective antibodies in mice. Similar Ogawa conjugates but with a longer linker that connects the carrier to shorter saccharides are immunogenic, but generally ineffective at inducing vibriocidal or protective antibodies. The efficacy of Ogawa Hexasaccharide neoglycoconjugates of different linker lengths were tested. The majority of mice given immunizations separated by a 14-day gap did not produce vibriocidal or protective antibodies. Mice immunized 28 days apart with immunogens containing the shortest or medium length linker, but not the longest, produced vibriocidal and protective antibodies. A nonprotective, priming dose of purified Ogawa LPS followed 5 days later with a booster of the Ogawa neoglycoconjugates (di-, tetra-, or Hexasaccharide) resulted in vibriocidal antibodies at day 10.
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synthetic fragments of vibrio cholerae o1 inaba o specific polysaccharide bound to a protein carrier are immunogenic in mice but do not induce protective antibodies
Infection and Immunity, 2004Co-Authors: Michael D Meeks, Rina Saksena, Terri K. Wade, Pavol Kováč, Ronald K Taylor, William F. WadeAbstract:Development of Vibrio cholerae lipopolysaccharide (LPS) as a cholera vaccine immunogen is justified by the correlation of vibriocidal anti-LPS response with immunity. Two V. cholerae O1 LPS serotypes, Inaba and Ogawa, are associated with endemic and pandemic cholera. Both serotypes induce protective antibody following infection or vaccination. Structurally, the LPSs that define the serotypes are identical except for the terminal perosamine moiety, which has a methoxyl group at position 2 in Ogawa but a hydroxyl group in Inaba. The terminal sugar of the Ogawa LPS is a protective B-cell epitope. We chemically synthesized the terminal Hexasaccharides of V. cholerae serotype Ogawa, which comprises in part the O-specific polysaccharide component of the native LPS, and coupled the oligosaccharide at different molar ratios to bovine serum albumin (BSA). Our initial studies with Ogawa immunogens showed that the conjugates induced protective antibody. We hypothesized that antibodies specific for the terminal sugar of Inaba LPS would also be protective. Neoglycoconjugates were prepared from synthetic Inaba oligosaccharides (disaccharide, tetrasaccharide, and Hexasaccharide) and BSA at different levels of substitution. BALB/c mice responded to the Inaba carbohydrate (CHO)-BSA conjugates with levels of serum antibodies of comparable magnitude to those of mice immunized with Ogawa CHO-BSA conjugates, but the Inaba-specific antibodies (immunoglobulin M [IgM] and IgG1) were neither vibriocidal nor protective in the infant mouse cholera model. We hypothesize that the anti-Inaba antibodies induced by the Inaba CHO-BSA conjugates have enough affinity to be screened via enzyme-linked immunosorbent assay but not enough to be protective in vivo.
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Neoglycoconjugates from synthetic tetra- and Hexasaccharides that mimic the terminus of the O-PS of Vibrio cholerae O:1, serotype Inaba
Organic & Biomolecular Chemistry, 2003Co-Authors: Rina Saksena, Anatoly Ya. Chernyak, Pavol KováčAbstract:A glycosyl acceptor and a glycosyl donor having the N-3-deoxy-L-glycero-tetronic acid side chain already attached have been prepared and used for the synthesis of the di- through to the Hexasaccharide that mimic the upstream terminus of the O-specific polysaccharide of Vibrio cholerae O:1, serotype Inaba. The target tetra- and the Hexasaccharide, which were obtained in the form of 5-methoxycarbonylpentyl glycosides, were linked to BSA using squaric acid diester chemistry. The conjugation reactions were monitored by surface enhanced laser desorption ionization-time of flight mass spectrometry (SELDI-TOF MS). This allowed the progression of the conjugation of the synthetic oligosaccharides in a controlled way and termination of the reaction when the desired molar hapten/BSA ratio had been reached, yielding neoglycoconjugates with predetermined carbohydrate/carrier ratios. The ability to monitor the conjugation by the SELDI-TOF MS technique made it possible to prepare, from one hapten in a one-pot reaction, several neoglycoconjugates having different, predetermined carbohydrate/carrier ratios.
Carola Gallorodriguez - One of the best experts on this subject based on the ideXlab platform.
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synthesis of the Hexasaccharide from trypanosoma cruzi mucins with the galp 1 2 galf unit constructed with a superarmed thiogalactopyranosyl donor
Carbohydrate Research, 2019Co-Authors: Gustavo A. Kashiwagi, Carmen R. Cori, Rosa M. De Lederkremer, Carola GallorodriguezAbstract:Abstract Hexasaccharide β-D-Galp-(1→ 2)-[β-D-Galp-(1 → 3)]-β-D-Galp-(1 → 6)-[β-D-Galp-(1 → 2)-β-D-Galf-(1 → 4)]-D-GlcNAc (1) was found O-linked in mucins of Trypanosoma cruzi epimastigotes and metacyclic trypomatigotes. Studies on the biological pathways and functionalities of the mucin oligosaccharides are prompted in order to understand the interactions of these molecules with the insect host. Trisaccharide constituent β-D-Galp-(1 → 2)-β-D-Galf-(1 → 4)-D-GlcNAc was constructed from the reducing to the non-reducing end. We discuss the difficulties to introduce a Galp unit at the O-2 position of a partially protected galactofuranosyl unit which were overcome using an anchimerically superarmed donor. By this route and employing a [3 + 3] nitrilium convergent approach Hexasaccharide 1 was synthesized in moderate yield.
Peter H Seeberger - One of the best experts on this subject based on the ideXlab platform.
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Total synthesis of a Streptococcus pneumoniae serotype 12F CPS repeating unit Hexasaccharide.
Beilstein Journal of Organic Chemistry, 2017Co-Authors: Peter H Seeberger, Claney L. Pereira, Subramanian GovindanAbstract:The Gram-positive bacterium Streptococcus pneumoniae causes severe disease globally. Vaccines that prevent S. pneumoniae infections induce antibodies against epitopes within the bacterial capsular polysaccharide (CPS). A better immunological understanding of the epitopes that protect from bacterial infection requires defined oligosaccharides obtained by total synthesis. The key to the synthesis of the S. pneumoniae serotype 12F CPS Hexasaccharide repeating unit that is not contained in currently used glycoconjugate vaccines is the assembly of the trisaccharide β-D-GalpNAc-(1→4)-[α-D-Glcp-(1→3)]-β-D-ManpNAcA, in which the branching points are equipped with orthogonal protecting groups. A linear approach relying on the sequential assembly of monosaccharide building blocks proved superior to a convergent [3 + 3] strategy that was not successful due to steric constraints. The synthetic Hexasaccharide is the starting point for further immunological investigations.
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synthesis of a Hexasaccharide repeating unit from bacillus anthracis vegetative cell walls
Organic Letters, 2008Co-Authors: Matthias A Oberli, Pascal Bindschadler, Daniel B Werz, Peter H SeebergerAbstract:The first synthesis of Hexasaccharide 1 representing a repeat unit of a polysaccharide specific to the vegetative cell wall of Bacillus anthracis is reported. The synthetic Hexasaccharide is equipp...
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Synthesis of a Hexasaccharide repeating unit from Bacillus anthracis vegetative cell walls.
Organic Letters, 2008Co-Authors: Matthias A Oberli, Pascal Bindschadler, Daniel B Werz, Peter H SeebergerAbstract:The first synthesis of Hexasaccharide 1 representing a repeat unit of a polysaccharide specific to the vegetative cell wall of Bacillus anthracis is reported. The synthetic Hexasaccharide is equipped with an n-pentenyl handle at the reducing terminus to allow for further functionalization. Key transformations during the synthesis are the conversion of a glucose into a mannosazide residue, a (2+2) coupling, followed by double α-galactosylation to furnish the Hexasaccharide, and global deprotection under Birch conditions.
Gustavo A. Kashiwagi - One of the best experts on this subject based on the ideXlab platform.
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synthesis of the Hexasaccharide from trypanosoma cruzi mucins with the galp 1 2 galf unit constructed with a superarmed thiogalactopyranosyl donor
Carbohydrate Research, 2019Co-Authors: Gustavo A. Kashiwagi, Carmen R. Cori, Rosa M. De Lederkremer, Carola GallorodriguezAbstract:Abstract Hexasaccharide β-D-Galp-(1→ 2)-[β-D-Galp-(1 → 3)]-β-D-Galp-(1 → 6)-[β-D-Galp-(1 → 2)-β-D-Galf-(1 → 4)]-D-GlcNAc (1) was found O-linked in mucins of Trypanosoma cruzi epimastigotes and metacyclic trypomatigotes. Studies on the biological pathways and functionalities of the mucin oligosaccharides are prompted in order to understand the interactions of these molecules with the insect host. Trisaccharide constituent β-D-Galp-(1 → 2)-β-D-Galf-(1 → 4)-D-GlcNAc was constructed from the reducing to the non-reducing end. We discuss the difficulties to introduce a Galp unit at the O-2 position of a partially protected galactofuranosyl unit which were overcome using an anchimerically superarmed donor. By this route and employing a [3 + 3] nitrilium convergent approach Hexasaccharide 1 was synthesized in moderate yield.
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Synthesis of the Hexasaccharide from Trypanosoma cruzi mucins with the Galp(1 → 2)Galf unit constructed with a superarmed thiogalactopyranosyl donor.
Carbohydrate Research, 2019Co-Authors: Gustavo A. Kashiwagi, Carmen R. Cori, Rosa M. De Lederkremer, Carola Gallo-rodriguezAbstract:Abstract Hexasaccharide β-D-Galp-(1→ 2)-[β-D-Galp-(1 → 3)]-β-D-Galp-(1 → 6)-[β-D-Galp-(1 → 2)-β-D-Galf-(1 → 4)]-D-GlcNAc (1) was found O-linked in mucins of Trypanosoma cruzi epimastigotes and metacyclic trypomatigotes. Studies on the biological pathways and functionalities of the mucin oligosaccharides are prompted in order to understand the interactions of these molecules with the insect host. Trisaccharide constituent β-D-Galp-(1 → 2)-β-D-Galf-(1 → 4)-D-GlcNAc was constructed from the reducing to the non-reducing end. We discuss the difficulties to introduce a Galp unit at the O-2 position of a partially protected galactofuranosyl unit which were overcome using an anchimerically superarmed donor. By this route and employing a [3 + 3] nitrilium convergent approach Hexasaccharide 1 was synthesized in moderate yield.
Umesh R. Desai - One of the best experts on this subject based on the ideXlab platform.
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a Hexasaccharide containing rare 2 o sulfate glucuronic acid residues selectively activates heparin cofactor ii
Angewandte Chemie, 2017Co-Authors: Nehru Viji Sankaranarayanan, Arjun Raghuraman, Philip D Mosier, Rio S Boothello, Tamara R Strebel, Kevin Sheerin, Florence Sallas, Nicholas D Watermeyer, Stefan Oscarson, Umesh R. DesaiAbstract:Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate Hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2-O-sulfate residues as selectively targeting HCII. This and four other unique Hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250-fold, while leaving aside antithrombin, a closely related serpin, essentially unactivated. This group of rare designed Hexasaccharides will help understand HCII function. More importantly, our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAG sequences that can selectively target GAG-binding protein(s), which may lead to chemical biology or drug discovery tools.
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A Hexasaccharide Containing Rare 2‐O‐Sulfate‐Glucuronic Acid Residues Selectively Activates Heparin Cofactor II
Angewandte Chemie International Edition, 2017Co-Authors: Nehru Viji Sankaranarayanan, Arjun Raghuraman, Philip D Mosier, Rio S Boothello, Tamara R Strebel, Kevin Sheerin, Florence Sallas, Nicholas D Watermeyer, Stefan Oscarson, Umesh R. DesaiAbstract:Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate Hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2-O-sulfate residues as selectively targeting HCII. This and four other unique Hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250-fold, while leaving aside antithrombin, a closely related serpin, essentially unactivated. This group of rare designed Hexasaccharides will help understand HCII function. More importantly, our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAG sequences that can selectively target GAG-binding protein(s), which may lead to chemical biology or drug discovery tools.
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heparan sulfate Hexasaccharide selectively inhibits cancer stem cells self renewal by activating p38 map kinase
Oncotarget, 2016Co-Authors: Nirmita J Patel, Umesh R. Desai, Chetna Sharon, Somesh Baranwal, Rio S Boothello, Bhaumik B PatelAbstract:// Nirmita J. Patel 1, 3 , Chetna Sharon 1 , Somesh Baranwal 1, 2 , Rio S. Boothello 1, 2 , Umesh R. Desai 3 , Bhaumik B. Patel 1, 2 1 Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA 2 Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA 3 Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA Correspondence to: Bhaumik B. Patel, email: bhaumik.patel@vcuhealth.org Keywords: cancer stem cells, colorectal cancer, glycosaminoglycans, p38 mitogen activated protein kinase, heparan sulfate Received: June 17, 2016 Accepted: September 05, 2016 Published: September 30, 2016 ABSTRACT Heparan sulfate (HS) plays a role in the majority of essential hallmarks of cancer, yet its ability to modulate self-renewal, especially of cancer stem cells (CSCs), remains unknown. We have discovered that a non-anticoagulant HS Hexasaccharide (HS06) sequence, but not other shorter or longer sequences, selectively inhibited CSC self-renewal and induced apoptosis in colorectal, pancreatic, and breast CSCs suggesting a very general phenomenon. HS06 inhibition of CSCs relied upon early and sustained activation of p38α/β mitogen activated protein kinase (MAPK) but not other MAPKs family members i.e. ERK and JNK. In contrast, polymeric HS induced exactly opposite changes in MAPK activation and failed to inhibit CSCs. In fact, TCF4 signaling, a critical regulator of CSC self-renewal, was inhibited by HS06 in a p38 activation dependent fashion. In conclusion, HS06 selectively inhibits CSCs self-renewal by causing isoform specific activation of p38MAPK to inhibit TCF4 signaling. These observations on chain length-induced specificity carry major mechanistic implications with regard to HS in cancer biology, while also presenting a novel paradigm for developing novel anti-CSC Hexasaccharides that prevent cancer relapse. STATEMENT OF SIGNIFICANCE Heparan sulfate (HS) of specific length, i.e., Hexasaccharide (HS06), but not longer or shorter sequences, selectively inhibit cancer stem cells (CSCs) through isoform specific activation of p38 mitogen-activated protein kinase. These findings will have major implication for developing chemical probes to decipher complex signaling events that govern cancer stem cells. Additionally, there are direct implications for designing glycosaminoglycan based cancer therapies to selectively target CSCs that escape killing by traditional chemotherapy threatening cancer relapse.
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understanding dermatan sulfate heparin cofactor ii interaction through virtual library screening
ACS Medicinal Chemistry Letters, 2010Co-Authors: Arjun Raghuraman, Philip D Mosier, Umesh R. DesaiAbstract:Dermatan sulfate, an important member of the glycosaminoglycan family, interacts with heparin cofactor II, a member of the serpin family of proteins, to modulate antithrombotic response. Yet, the nature of this interaction remains poorly understood at a molecular level. We report the genetic algorithm-based combinatorial virtual library screening study of a natural, high-affinity dermatan sulfate Hexasaccharide with heparin cofactor II. Of the 192 topologies possible for the Hexasaccharide, only 16 satisfied the “high-specificity” criteria used in computational study. Of these, 13 topologies were predicted to bind in the heparin-binding site of heparin cofactor II at a ∼60° angle to helix D, a novel binding mode. This new binding geometry satisfies all known solution and mutagenesis data and supports thrombin ternary complexation through a template mechanism. The study is expected to facilitate the design of allosteric agonists of heparin cofactor II as antithrombotic agents.