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1. (CSDB ID: 8553) | report error |
| R-3HOMyr-(1-2)-+ | Myr-(1-3)-R-3HOMyr-(1-3)-+ | | | Lau-(1-3)-R-3HOMyr-(1-2)-b-D-GlcpN-(1-6)-a-D-GlcpN-(1-P | | P-4)-+ | | R-3HOMyr-(1-3)-+ | Show graphically |
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Escherichia coli
(NCBI TaxID 562,
species name lookup)
]
boku.ac.at>TLR4 is a key pattern recognition receptor that can sense pathogen- and danger- associated molecular patterns to activate the downstream signaling pathways which results in the upregulation of transcription factors and expression of interferons and cytokines to mediate protective pro-inflammatory responses involved in immune defense. Bacterial lipid A is the primary TLR4 ligand with very complex, species-specific, and barely predictable structure-activity relationships. Given that therapeutic targeting of TLR4 is an emerging tool for management of a variety of human diseases, the development of novel TLR4 activating biomolecules other than lipid A is of vast importance. We report on design, chemical synthesis and immunobiology of novel glycan-based lipid A-mimicking molecules that can activate human and murine TLR4-mediated signaling with picomolar affinity. Exploiting crystal structure - based design we have created novel disaccharide lipid A mimetics (DLAMs) where the inherently flexible β(1→6)-linked diglucosamine backbone of lipid A is exchanged with a conformationally restrained non-reducing βGlcN(1↔1')βGlcN scaffold. Excellent stereoselectivity in a challenging β,β-1,1' glycosylation was achieved by tuning the reactivities of donor and acceptor molecules using protective group manipulation strategy. Divergent streamlined synthesis of β,β-1,1'-linked diglucosamine-derived glycolipids entailing multiple long-chain (R)-3- acyloxyacyl residues and up two three phosphate groups was developed. Specific 3D-molecular shape and conformational rigidity of unnatural β,β-1,1'-linked diglucosamine combined with carefully optimized phosphorylation and acylation pattern ensured efficient induction of the TLR4-mediated signaling in a species-independent manner.
Lipopolysaccharide, carbohydrates, lipid A, glycosylation, adjuvant, modulation of the innate immune responses
Structure type: oligomer|
2. (CSDB ID: 8830) | report error |
| Lau-(1-3)-3HOMyr-(1-2)-+ | 3HOLau-(1-3)-+ | | | Lau-(1-3)-3HOMyr-(1-2)-b-D-GlcpN-(1-6)-a-D-GlcpN-(1-P | | P-4)-+ 3HOLau-(1-3)-+ | Show graphically |
|
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Neisseria meningitidis
(NCBI TaxID 487,
species name lookup)
]boku.ac.at>TLR4 is a key pattern recognition receptor that can sense pathogen- and danger- associated molecular patterns to activate the downstream signaling pathways which results in the upregulation of transcription factors and expression of interferons and cytokines to mediate protective pro-inflammatory responses involved in immune defense. Bacterial lipid A is the primary TLR4 ligand with very complex, species-specific, and barely predictable structure-activity relationships. Given that therapeutic targeting of TLR4 is an emerging tool for management of a variety of human diseases, the development of novel TLR4 activating biomolecules other than lipid A is of vast importance. We report on design, chemical synthesis and immunobiology of novel glycan-based lipid A-mimicking molecules that can activate human and murine TLR4-mediated signaling with picomolar affinity. Exploiting crystal structure - based design we have created novel disaccharide lipid A mimetics (DLAMs) where the inherently flexible β(1→6)-linked diglucosamine backbone of lipid A is exchanged with a conformationally restrained non-reducing βGlcN(1↔1')βGlcN scaffold. Excellent stereoselectivity in a challenging β,β-1,1' glycosylation was achieved by tuning the reactivities of donor and acceptor molecules using protective group manipulation strategy. Divergent streamlined synthesis of β,β-1,1'-linked diglucosamine-derived glycolipids entailing multiple long-chain (R)-3- acyloxyacyl residues and up two three phosphate groups was developed. Specific 3D-molecular shape and conformational rigidity of unnatural β,β-1,1'-linked diglucosamine combined with carefully optimized phosphorylation and acylation pattern ensured efficient induction of the TLR4-mediated signaling in a species-independent manner.
Lipopolysaccharide, carbohydrates, lipid A, glycosylation, adjuvant, modulation of the innate immune responses
Structure type: oligomer|
3. (CSDB ID: 8831) | report error |
| Pam-(1-3)-R-3HOMyr-(1-2)-+ | Myr-(1-3)-R-3HOMyr-(1-3)-+ | | | Lau-(1-3)-R-3HOMyr-(1-2)-b-D-GlcpN-(1-6)-a-D-GlcpN-(1-P | | P-4)-+ | | R-3HOMyr-(1-3)-+ | Show graphically |
|
Show legend Show as text |
Salmonella minnesota
(later renamed to: Salmonella enterica ssp. enterica sv. Minnesota)
(NCBI TaxID 70803,
species name lookup)
]boku.ac.at>TLR4 is a key pattern recognition receptor that can sense pathogen- and danger- associated molecular patterns to activate the downstream signaling pathways which results in the upregulation of transcription factors and expression of interferons and cytokines to mediate protective pro-inflammatory responses involved in immune defense. Bacterial lipid A is the primary TLR4 ligand with very complex, species-specific, and barely predictable structure-activity relationships. Given that therapeutic targeting of TLR4 is an emerging tool for management of a variety of human diseases, the development of novel TLR4 activating biomolecules other than lipid A is of vast importance. We report on design, chemical synthesis and immunobiology of novel glycan-based lipid A-mimicking molecules that can activate human and murine TLR4-mediated signaling with picomolar affinity. Exploiting crystal structure - based design we have created novel disaccharide lipid A mimetics (DLAMs) where the inherently flexible β(1→6)-linked diglucosamine backbone of lipid A is exchanged with a conformationally restrained non-reducing βGlcN(1↔1')βGlcN scaffold. Excellent stereoselectivity in a challenging β,β-1,1' glycosylation was achieved by tuning the reactivities of donor and acceptor molecules using protective group manipulation strategy. Divergent streamlined synthesis of β,β-1,1'-linked diglucosamine-derived glycolipids entailing multiple long-chain (R)-3- acyloxyacyl residues and up two three phosphate groups was developed. Specific 3D-molecular shape and conformational rigidity of unnatural β,β-1,1'-linked diglucosamine combined with carefully optimized phosphorylation and acylation pattern ensured efficient induction of the TLR4-mediated signaling in a species-independent manner.
Lipopolysaccharide, carbohydrates, lipid A, glycosylation, adjuvant, modulation of the innate immune responses
Structure type: oligomer|
4. (CSDB ID: 8832) | report error |
| Pam-(1-3)-R-3HOMyr-(1-2)-+ | Myr-(1-3)-R-3HOMyr-(1-3)-+ | | | Lau-(1-3)-R-3HOMyr-(1-2)-b-D-GlcpN-(1-6)-D-GlcpN | P-4)-+ | Show graphically |
|
Show legend Show as text |
Salmonella minnesota
(later renamed to: Salmonella enterica ssp. enterica sv. Minnesota)
(NCBI TaxID 70803,
species name lookup)
]boku.ac.at>TLR4 is a key pattern recognition receptor that can sense pathogen- and danger- associated molecular patterns to activate the downstream signaling pathways which results in the upregulation of transcription factors and expression of interferons and cytokines to mediate protective pro-inflammatory responses involved in immune defense. Bacterial lipid A is the primary TLR4 ligand with very complex, species-specific, and barely predictable structure-activity relationships. Given that therapeutic targeting of TLR4 is an emerging tool for management of a variety of human diseases, the development of novel TLR4 activating biomolecules other than lipid A is of vast importance. We report on design, chemical synthesis and immunobiology of novel glycan-based lipid A-mimicking molecules that can activate human and murine TLR4-mediated signaling with picomolar affinity. Exploiting crystal structure - based design we have created novel disaccharide lipid A mimetics (DLAMs) where the inherently flexible β(1→6)-linked diglucosamine backbone of lipid A is exchanged with a conformationally restrained non-reducing βGlcN(1↔1')βGlcN scaffold. Excellent stereoselectivity in a challenging β,β-1,1' glycosylation was achieved by tuning the reactivities of donor and acceptor molecules using protective group manipulation strategy. Divergent streamlined synthesis of β,β-1,1'-linked diglucosamine-derived glycolipids entailing multiple long-chain (R)-3- acyloxyacyl residues and up two three phosphate groups was developed. Specific 3D-molecular shape and conformational rigidity of unnatural β,β-1,1'-linked diglucosamine combined with carefully optimized phosphorylation and acylation pattern ensured efficient induction of the TLR4-mediated signaling in a species-independent manner.
Lipopolysaccharide, carbohydrates, lipid A, glycosylation, adjuvant, modulation of the innate immune responses
Structure type: oligomer| New query | Export IDs | Home | Help |
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