Total synthesis, structural and biological studies of fragments of t-cell dependent antigen zwitterionic polysaccharide sp1

Session: 
S1.2 Bacterial glycan synthesis
Code: 
OL1.2.1
Location (hall): 
Mannose
Start/end time: 
Monday, July 1, 2019 - 11:45 to 12:00
Zhen
Wang

Zhen Wang1, Qingju Zhang2, Ana Gimeno3, Darielys Santana4, Yury Valdes-Balbin4, Dagmar García Rivera4, Thomas Hansen1, Herman S.  Overkleeft1, Jesús Jiménez-Barbero3, Vicente Vérez-Bencomo4, Fabrizio Chiodo5, Gijs van der Marel1, Jeroen Codée1

1Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands, 2National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang, China, 3CIC bioGUNE, Derio, Spain, 4Finlay Vaccine Institute, Havana, Cuba, 5Amsterdam infection and immunity institute, Amsterdam UMC, Amsterdam, The Netherlands

Typically, bacterial capsular polysaccharides are considered to be “T-cell-independent antigens” which cannot be used in a vaccine setting, leading to immunological memory, without conjugating to a protein. Zwitterionic polysaccharides (ZPSs) are a rare class of immunomodulatory agents that can provoke a T-cell mediated immune responses through MHC II binding and CD4+ T-cell activation.[1] Zwitterionic polysaccharide Sp1, isolated from the human pathogen Streptococcus pneumoniae, contains repeating units of the trisaccharide below (Figure A).[2] To explore its detailed structure–activity relationship (SAR) and immunomodulatory mechanism, well-defined oligosaccharides of Sp1 are required. The synthesis of Sp1 oligosaccharides is extremely challenging because of the presence of rare monosaccharide constituents (such as trideoxy-diaminogalactose residues), the 1,2-cis-glycosidic bonds, and both positive and negative charges.[3]

Here, we report the synthesis of various oligosaccharide fragments with a varying number of repeating units, with and without O-acetyl groups, using both pre- and post-glycosylation oxidation strategy. We also present its structural studies (molecular dynamics (MD), Molecular Modeling) and the biological evaluation on these  ZPS oligosaccharides. Finally, using STD-NMR (Figure B and C), we found that the synthetic Sp1 analogues interact with an anti-Sp1 monoclonal antibody via a groove-type site topology in an extended binding mode.

Figure. A) The targets structure of the Sp1. B) Structure of dodecamer. The relative STD effect for non-overlapped protons is indicated by colors. C) Structure of dodecamer, in which the relative STD effect for overlapped protons was equally distributed.

References: 
  1. Mazmanian S. K.; Kasper D. L., Nat. Rev. Immunol., 2006, 6, 849-858.
  2. Stroop, C. J. M.; Xu, Q.; Retzlaff, M.; Abeygunawardana, C.; Bush, C. A., S, Carbohydr. Res. 2002, 337, 335-344.
  3. a) Wu, X.; Cui, L.; Lipinski, T.; Bundle, D. R., Chem.Eur. J. 2010, 16, 3476-3488. b) Christina A. E.; van den Bos L. J.; Overkleeft H. S.; van der Marel G. A.; Codée J. D. C., J. Org. Chem. 2011, 76, 1692-1706.

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