Synthetic Lipid A mimetics for exploration of LPS recognition by the proteins of innate immune system
Abstract
Recognition of the endotoxic portion of the Gram-negative bacterial lipopolysaccharide (LPS), a glycophospholipid Lipid A, by the transmembrane protein complex Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD-2) and by the intracellular serine protease Caspase-4/11 initiates activation of the pro-inflammatory signaling cascade and is essential for the control of infectious diseases. Activation of TLR4 was also shown to bridge the innate and adaptive immunity, which highlights stimulation of TLR4 complex by the non-pyrogenic ligands as a useful approach for development of novel vaccine adjuvants. Though, LPS-induced TLR4 signaling may result in the development of a dysregulated innate immune response leading to variety of inflammatory conditions. To explore the molecular basis for Lipid A – induced Caspase-4/11 (non-canonical TLR4-independent inflammasome activation) and TLR4 activation, chemical synthesis and immuno-functional studies of innovative conformationally confined Lipid A mimetics is intended. Lipid A is composed of a 1,4′ -bisphosphorylated βGlcN(1→6)GlcN polar head group which carries a variable number of long-chain (R)-3-hydroxyacyl- and (R)-3-acyloxyacyl residues in symmetric or asymmetric distribution. Synthesis of Lipid A mimetics wherein the flexible three-bond β(1→6) connection is exchanged for a rigid two-bond (1↔1) glycosidic linkage will provide potentially agonistic Caspase-4/11 and TLR4 ligands. Restricting conformational flexibility of Lipid A by fixing the molecular shape of its carbohydrate backbone in a predefined conformation attained by a rigid (1↔1)-linked disaccharide scaffold would allow to attain a specific topology of the functional groups of the ligands (phosphates and long-chain (R)-3-acyloxyacyl residues) in the ligand-protein complexes. Evaluation of the tetriary structure of the ligand in respect to its immuno-stimulating activity will ensure a reliable correlation of structure-activity relationships.
keywords Glycochemistry Innate Immunity Bacterial Lipopolysaccharide Structure-activity relationships Bacterial Glycans
Publikationen
Stereoselective synthesis of the innate immune modulator D-glycero-ß-D-manno-heptose-1,7-bisphosphate
Autoren: Borio, A; Kosma, P; Zamyatina, A. Jahr: 2017
Conference & Workshop proceedings, paper, abstract
Synthesis of conformationally restricted lipid A mimetics
Autoren: Borio, A; Zamyatina, A: Jahr: 2017
Conference & Workshop proceedings, paper, abstract
Chemical synthesis of both isomers of bacterial metabolite D-glycero-D-manno-heptose-1,7-bisphosphate
Autoren: Borio, A; Kosma, P; Zamyatina, A. Jahr: 2017
Conference & Workshop proceedings, paper, abstract
ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System.
Autoren: Zimmermann, S; Pfannkuch, L; Al-Zeer, MA; Bartfeld, S; Koch, M; Liu, J; Rechner, C; Soerensen, M; Sokolova, O; Zamyatina, A; Kosma, P; Mäurer, AP; Glowinski, F; Pleissner, KP; Schmid, M; Brinkmann, V; Karlas, A; Naumann, M; Rother, M; Machuy, N; Meyer, TF; Jahr: 2017
Journal articles
Chemical synthesis of the innate immune modulator - bacterial D-glycero-beta-D-manno-heptose-1,7-bisphosphate (HBP)
Autoren: Borio, A; Hofinger, A; Kosma, P; Zamyatina, A Jahr: 2017
Journal articles
Aminosugar-based immunomodulator lipid A: synthetic approaches.
Autoren: Zamyatina, A; Jahr: 2018
Journal articles
Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics.
Autoren: Adanitsch, F; Shi, J; Shao, F; Beyaert, R; Heine, H; Zamyatina, A; Jahr: 2018
Journal articles
Stereoselective ß,ß-1,1' glycosylation towards orthogonally protected diglucosamine derivatives
Autoren: Strobl, S; Zamyatina, A. Jahr: 2018
Conference & Workshop proceedings, paper, abstract
Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose.
Autoren: Zhou, P; She, Y; Dong, N; Li, P; He, H; Borio, A; Wu, Q; Lu, S; Ding, X; Cao, Y; Xu, Y; Gao, W; Dong, M; Ding, J; Wang, DC; Zamyatina, A; Shao, F; Jahr: 2018
Journal articles
Disaccharide-Based Anionic Amphiphiles as Potent Inhibitors of Lipopolysaccharide-Induced Inflammation.
Autoren: Borio, A; Holgado, A; Garate, JA; Beyaert, R; Heine, H; Zamyatina, A; Jahr: 2018
Journal articles
Modulation of TLR4 signaling with synthetic lipid A mimetics
Autoren: Heine, H; Zamyatina, A Jahr: 2018
Conference & Workshop proceedings, paper, abstract
ADP-heptose is a newly identified pathogen-associated molecular pattern of
Autoren: García-Weber, D; Dangeard, AS; Cornil, J; Thai, L; Rytter, H; Zamyatina, A; Mulard, LA; Arrieumerlou, C; Jahr: 2018
Journal articles
Stereoselective ß,ß-1.1' glycosylation for the synthesis of lipid A mimetics
Autoren: Strobl, S; Hofbauer, K; Zamaytina, A. Jahr: 2019
Conference & Workshop proceedings, paper, abstract
Synthetic 1,1'-linked disaccharide-based glycolipids for immunomodulation
Autoren: Zamyatina, A. Jahr: 2019
Conference & Workshop proceedings, paper, abstract
Shortening the Lipid A Acyl Chains of Bordetella pertussis Enables Depletion of Lipopolysaccharide Endotoxic Activity
Autoren: Arenas, J; Pupo, E; Phielix, C; David, D; Zariri, A; Zamyatina, A; Tommassen, J; van der Ley, P; Jahr: 2020
Journal articles
Synthesis of bioactive lipid A and analogs
Autoren: Alla Zamyatina; Sebastian Strobl Jahr: 2020
Chapter in collected volumes
Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways.
Autoren: Zamyatina, A; Heine, H; Jahr: 2020
Journal articles
Corrigendum: Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways.
Autoren: Zamyatina, A; Heine, H; Jahr: 2021
Journal articles
Tailored Modulation of Cellular Pro-inflammatory Responses With Disaccharide Lipid A Mimetics.
Autoren: Heine, H; Adanitsch, F; Peternelj, TT; Haegman, M; Kasper, C; Ittig, S; Beyaert, R; Jerala, R; Zamyatina, A; Jahr: 2021
Journal articles
Rational Vaccine Design in Times of Emerging Diseases: The Critical Choices of Immunological Correlates of Protection, Vaccine Antigen and Immunomodulation.
Autoren: Schijns, V; Majhen, D; van der Ley, P; Thakur, A; Summerfield, A; Berisio, R; Nativi, C; Fernández-Tejada, A; Alvarez-Dominguez, C; Gizurarson, S; Zamyatina, A; Molinaro, A; Rosano, C; Jakopin, Ž; Gursel, I; McClean, S; Jahr: 2021
Journal articles
Orchestrating TLR4 signaling and caspase-4/11 activation with endotoxin mimetics
Autoren: Alla Zamyatina Jahr: 2020
Conference & Workshop proceedings, paper, abstract
Project staff
Alla Zamyatina
Assoc. Prof. Dipl.-Ing. Dr. Alla Zamyatina
alla.zamyatina@boku.ac.at
Tel: +43 1 47654-77384
Project Leader
01.06.2016 - 30.10.2020