Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
Associated disease: infection due to Salmonella enterica [ICD11:
XN5VC 
]
NCBI PubMed ID: 35439332Publication DOI: 10.1002/chem.202200547Journal NLM ID: 9513783Publisher: Weinheim: VCH Verlagsgesellschaft/Verlag I
Correspondence: A. Zamyatina <alla.zamyatina
boku.ac.at>
Institutions: Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, Vienna, 1190, Austria, Research Group Innate Immunity, Research Center Borstel-Leibniz Lung Center, Airway Research Center North (ARCN), German Center for Lung Disease (DZL), Parkallee 22, Borstel, 23845, Germany
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
Location inside paper: Fig. 1A, heptaacyl S. minnesota lipid A
Compound class: lipid A
Contained glycoepitopes: IEDB_135394,IEDB_137340,IEDB_141181,IEDB_141807,IEDB_151531,IEDB_176772,IEDB_534864
Methods: 13C NMR, 1H NMR, TLC, 31P NMR, chemical synthesis, chemical methods, MALDI-TOF MS, HPLC, optical rotation measurement, SEC, HR-ESI-MS, immunobiology
3D data: 3D data
Related record ID(s): 8553, 8830, 8832
NCBI Taxonomy refs (TaxIDs): 70803
Show glycosyltransferases
There is only one chemically distinct structure:
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(later renamed to: Salmonella enterica ssp. enterica sv. Minnesota)