Preparation of Mimetics Synthetic Heparan Sulfates Long Fragments with Different Topologies

Session: 
PS1 Poster session 1 Odd numbers
Code: 
P135
Location (hall): 
Foyer
Start/end time: 
Monday, July 1, 2019 - 15:45 to 17:15
Junjun
Ma

Junjun Ma1, Wenqing Liu1, Christine Le Narvor1, Aurélien Alix1, David Bonnaffé1

1Universite Paris-Sud, Orsay, France

Heparan sulfates (HS) are linear polysulfated polysaccharides composed of alternate 1,4-linked uronic acid (either β-D-glucuronic acid (GlcUA) or α-L-iduronic acid (IdoA)) and α-D-glucosamine (GlcN). HS are widespread on the cell surfaces and in the extracellular matrix, capable of mediating and/or modulating various physiological processes, including blood coagulation, tissue repair and remodeling, development, angiogenesis, and bacterial and viral infections.[1]

Interferon-γ(IFN-γ) is a cytokine that plays a vital role in the immune response and inflammatory processes.[2] IFN-γis composed of a C2-symmetric homodimer that binds to HS by virtue of its basic residues located at the C terminus of the two subunits.[3] We have shown that symmetric “head to head” HS mimetics, exhibiting also a C2-symmetry (Figure 1a) are nanomolar inhibitors of IFNγpro-inflammatory activity by preventing cytokine bonding both on HS and its receptor.[4] After validating the feasibility of reducing-end (RE) and non-reducing end (NRE) modifications by click chemistry on a disaccharide model, we will present the strategy allowing preparation of HS long fragments mimetics with “tail to tail” and “head to tail” topologies (Figure 1b and 1c).

Figure 1. Representations of three kinds of HS mimetics geometries for the study of HS/proteins interactions.

References: 
  1. a) I. Capila, R. J. Linhardt, Angew. Chem. Int. Ed. 2002, 41, 390-412; (b) H. Lortat Jacob, A. Grosdidier, A. Imberty, Proc. Natl. Acad.Sci. USA 2002, 99, 1229-1234; (c) Xu, D.; Esko, J. Annu. Rev. Biochem. 2014, 83, 129-157; (d) Bishop, J. R.; Schuksz, M.; Esko, J. D. Nature 2007, 446, 1030-1037.
  2. (a) H. Lortat-Jacob, H. K. Kleinman, J. A. Grimaud, J. Clin. Invest.1991, 87, 878-883; (b) H. Lortat-Jacob, C. Brisson, S. Guerret, G. Morel, Cytokine 1996, 8, 557-566; (c) H. Lortat-Jacob, F. Baltzer, J.A. Grimaud, J. Biol. Chem. 1996, 271, 16139-16143; (d) A. Lubineau, H. Lortat-Jacob, O. Gavard, S. Sarrazin, D. Bonnaffé, Chem. Eur. J. 2004, 10, 4265-4282; (e) D. Bonnaffé. C. R. Chimie 2011, 14, 29-73.
  3. H. Lortat-Jacob, J. A. Grimaud, FEBS Lett. 1991, 280, 152-154.
  4. S. Sarrazin, D. Bonnaffé, A. Lubineau, H. Lortat-Jacob, J. Biol. Chem. 2005, 280, 37558-37564.
Weight: 
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