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

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

Zhen Wang 1 , Qingju Zhang 2 , Ana Gimeno 3 , Darielys Santana 4 , Yury Valdes-Balbin 4 , Dagmar García Rivera 4 , Thomas Hansen 1 , Herman S. Overkleeft 1 , Jesús Jiménez-Barbero 3 , Vicente Vérez-Bencomo 4 , Fabrizio Chiodo 5 , Gijs van der Marel 1 , Jeroen Codée 1

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

Mazmanian S. K.; Kasper D. L., Nat. Rev. Immunol., 2006, 6, 849-858.

Stroop, C. J. M.; Xu, Q.; Retzlaff, M.; Abeygunawardana, C.; Bush, C. A., S, Carbohydr. Res. 2002, 337, 335-344.

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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