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Selected Publication:

Strobl, S; Hofbauer, K; Heine, H; Zamyatina, A.
(2022): Lipid A Mimetics Based on Unnatural Disaccharide Scaffold as Potent TLR4 Agonists for Prospective Immunotherapeutics and Adjuvants
CHEM-EUR J. 2022; 28(35), e202200547 FullText FullText_BOKU

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 beta(1 -> 6)-linked diglucosamine backbone of lipid A is exchanged with a conformationally restrained non-reducing beta GlcN(1 <-> 1 ')beta GlcN scaffold. Excellent stereoselectivity in a challenging beta,beta-1,1 ' glycosylation was achieved by tuning the reactivities of donor and acceptor molecules using protective group manipulation strategy. Divergent streamlined synthesis of beta,beta-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 beta,beta-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.
Authors BOKU Wien:
Hofbauer Karin
Strobl Sebastian
Zamyatina Alla
BOKU Gendermonitor:

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modulation of the innate immune responses

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