Forschung

Synthesis of HIV antigens

Attempts to use the densely packed carbohydrate shield of the HIV envelope for the development of vaccines have met with very limited success over the last 30 years. The main reason is related to the structural resemblance of the viral sugar coat with the mammalian glycans thereby preventing immune activation. Based on the structure of a cell wall component from a plant-pathogenic bacterium (Rhizobium radiobacter), the synthesis of several carbohydrate mimetics followed by conversion of the ligands into glycoconjugates was accomplished. The conjugates were then used to generate spe-cific anti-HIV antibodies. In a joint collaboration with research groups from Canada (Ralph Pantophlet, Simon Fraser University) and the US (Ian Wilson, Scripps) - funded by the National Institutes of Health (NIH), the Austrian Science Fund FWF and the Canadian Institutes of Health Research - it could be shown that the induced immune sera had neutralizing activity against 5 out of 7 HIV strains. In addition, the molecular details of the binding motifs of a lead compound complexed to a broadly neutralizing antibody of the PGT family were determined. This epitope is presently being extended by a conserved bacterial glycan to boost the immune response.

• J.-F. Bruxelle, T. Kirilenko, Q. Qureshi, N. Lu, N. Trattnig, P. Kosma, R. Pantophlet, Sci Reports, 2020, 10, 7582 (doi.org/10.1038/s41598-020-64500-8)

• N. Trattnig, M. Blaukopf, J-F. Bruxelle, R. Pantophlet, P. Kosma, J. Am. Chem Soc. 2019, 141, 7946–7954 (doi:10.1021/jacs.9b02872).

• R. Pantophlet, N, Trattnig, S. Murrell, N. Lu, D. Chau, C. Rempel, I. Wilson, P. Kosma, Nat. Commun. 2017, 8, 1601 (doi.org/10.1038/s41467-017-01640-y).

• N. Trattnig, J.-B. Farcet, A. Christler, P. Gritsch, R. Pantophlet, P. Kosma, J. Org. Chem. 2017, 82, 12346-12358 (dx.doi.org/10.1021/acs.joc.7b02172).

Structural and biosynthetic studies of bacterial secondary cell wall polymers

Secondary cell wall polysaccharides serve as anchors to immobilize bacterial surface layer (glyco)proteins. A fruitful collaboration in the framework of FWF funded projects with the glyconanobiotechnology group of Christina Schäffer (Department of Nanobiotechnology) has allowed to identify 4,6-O-pyruvylated ManNAc in a secondary cell wall polymer from Paenibacillus alvei as the main binding partner. Moreover, the ManNAc unit is bound to two mutually exclusive binding grooves, thereby supporting dynamic changes during bacterial cell wall assembly and cell division.

Antibiotic resistance

Resistance against antimicrobial drugs has become a major problem in clinical practice, and thus, the underlying mechanisms need to be overcome by the design and development of suitable compounds either via novel modes of action or by restoring sensitivity to common antibiotics as well as by supporting the innate immune response. One basic hypothesis is built on the fact that incomplete lipopolysaccharide molecules are quickly recognized and cleared by the immune system leading to the concept of antivirulence drugs. Specifically, synthesis of inhibitors acting on conserved biosynthetic pathways of bacterial heptoses may provide new modes of action for antimicrobial agents.

Structure elucidation of glycans by NMR spectroscopy

NMR spectroscopy is used to elucidate the structure of poly- and oligosaccharides from various sources, such as novel N-glycans from algae (in cooperation with Friedrich Altmann) as an example