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Gewählte Doctoral Thesis:

Nino Trattnig (2018): Synthesis and vaccine potential of novel oligomannosides against HIV-1.
Doctoral Thesis - Abteilung für Organische Chemie (DCH/OC), BOKU-Universität für Bodenkultur, pp 270. UB BOKU obvsg

Data Source: ZID Abstracts
Abstract:
Gp120, present on the surface of the human immunodeficiency virus (HIV), harbors clusters of oligomannose structures that are recognized by several broadly neutralizing antibodies and thus constitutes an important target for HIV-1 vaccine development. Lipooligosaccharide (LOS), isolated from the bacterium Rhizobium radiobacter Rv3, closely resembles these oligomannose structures present on Gp120 and immunization of wild-type mice with heat-killed bacteria elicited serum antibodies, which bound to monomeric Gp120. To determine the antigenic potential of glycan mimetics that contain features of the viral and bacterial structures, a library of novel oligomannosides based on the pentamannoside fragment αMan1.2αMan1.2αMan1.3[αMan1.6]Man was synthesized and elongated to give 4 heptasaccharides. The mannose ligands were extended with a spacer that allowed coupling to bovine serum albumin using various conjugation techniques. For proper antigen mimicry, monovalent ligands were transformed into multivalent dendrimers via click-chemistry. Several neoglycoconjugates showed binding to the HIV broadly neutralizing antibody 2G12, but notably a high relative binding affinity by members of the PGT128 and PGT130 neutralizing antibody families was observed with one heptamannoside. Immunization of Hu-Ab transgenic rats with this potential antigen further showed promising neutralizing activity against a selection of tier 2 HIV strains. Based on these results, the construction of bacterial mimetics containing a LPS core (GlcNAc2Kdo2) was initiated. Kdo residues were efficiently introduced using an α-selective isopropylidene protected Kdo fluoride donor. Elongation at the unreactive 5-OH position of Kdo was achieved by the design of a highly reactive, orthogonally protected mannose donor and further elongation with a mannosyl trisaccharide followed by global deprotection gave the central octasaccharide of Rhizobium radiobacter Rv3 LOS.

Betreuer: Kosma Paul
1. Berater: Zamyatina Alla
2. Berater: Schäffer Christina

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