Ass.Professor Dr. Alla Zamyatina

The main topic of our research is to comprehend the structural and molecular basis of recognition of Lipopolysaccharide, a Pathogen - associated Molecular Pattern of Gram-negative bacteria, by its mammalian Pattern Recognition Receptor, Toll-like Receptor 4. Lipopolysaccharide (LPS) counts to the foremost virulence factors of Gram-negative infection. A glycophospholipid Lipid A, an endotoxic portion of LPS, initiates activation of the innate immune system by binding to the Toll-like Receptor 4 (TLR4) – myeloid differentiation 2 (MD-2) complex. The central point of investigations focusses on elucidation of structure-activity relationships within homodimeric Lipid A/MD-2/TLR4 receptor complex.

Chemical synthesis and exploration of the immuno-biological properties of diverse Lipid A variants corresponding to complex naturally occurring bacterial LPS as well as specifically designed Lipid A mimetics.

Development of agonistic and antagonistic TLR4 ligands as potential immuno-modulating therapeutics and anti-sepsis drug candidates.
Syntetic Endotoxin Mimetics (Read more...)

Artner, D., Oblak, A., Ittig, S., Garate, J.A., Horvat, S., Arrieumerlou, C., Hofinger, A., Oostenbrink, C., Jerala, R., Kosma, P., and Zamyatina, A. (2013) Conformationally constrained Lipid A mimetics for exploration of structural basis of TLR4/MD-2 activation by lipopolysaccharide. ACS Chem.Biol. 8, 2423-2432.

Adanitsch, F., Ittig, S., Stöckl, J., Oblak, A., Haegman, M., Jerala, R., Beyaert, R., Kosma, P., and Zamyatina, A. (2014) Development of αGlcN(1↔1)αMan-Based Lipid A Mimetics as a Novel Class of Potent Toll-like Receptor 4 Agonists. J.Med.Chem. 57, 8056-8071.

Baum, D., Kosma, P., and Zamyatina, A. (2014) Synthesis of zwitterionic 1,1-α,α-glycosylphosphodiester: a partial structure of galactosamine-modified Francisella Lipid A. Org.Lett. 16, 3772-3775.

Hollaus, R.; Ittig, S.; Hofinger, A.; Haegman, M.; Beyaert, R.; Kosma, K.; Zamyatina, A. Chemical synthesis of Burkholderia Lipid A modified with glycosyl phosphodiester-linked 4-amino-4-deoxy-β-L-arabinose and its immunomodulatory potential. (2015), Chem. Eur. J. 21, 4102-4114

Garate, J. A.; Stöckl, J.; del Carmen Fernández-Alonso, M.; Artner, D.; Haegman, M.; Oostenbrink, C.; Jiménez-Barbero, J.; Beyaert, R.; Heine, H.; Kosma, P.; Zamyatina, A. Anti-endotoxic activity and structural basis for human MD-2•TLR4 antagonism of tetraacylated lipid A mimetics based on βGlcN(1↔1)αGlcN scaffold. (2015), Innate Immun. 21, 490-503

The synthesis of heptose-containing partial structures of the Core-region of LPS and their biosynthetic precursors allows for exploration of the LPS biosynthetic pathways.

Zamyatina, A.; Gronow, S.; Oertelt, C.; Puchberger, M.; Brade, H. and Kosma, P. (2000) Efficient chemical synthesis of the two anomers of ADP-L-glycero- and D-glycero-D-manno-heptopyranose allows the determination of the substrate specificities of bacterial heptosyltransferases. Angew. Chemie. Int. Ed. 39, 4150-4153.

Kneidinger, B.; Marolda, C.; Graninger, M.; Zamyatina, A.; McArthur, F.; Kosma, P.; Valvano, M.A. and Messner, P. (2002) Biosynthesis pathway of ADP-L-glycero-β-D-manno-heptose in Escherichia coli. J. Bacteriol. 184, 363-369.

Lu, Q.; Yao, Q.; Xu, Y.; Li, L.; Li, S.; Liu, Y.; Gao, W.; Niu, M.; Sharon, M.; Ben-Nissan, G.; Zamyatina, A.; Liu, X.; Chen, S. and Shao, F. (2014) An Iron-Containing Dodecameric Heptosyltransferase Family Modifies Bacterial Autotransporters in Pathogenesis. Cell Host & Microbe 16, 351-363