Chemical GAGobiology: optimized chemistry for tailored probes

Session: 
S8.4 Glycosaminoglycans
Code: 
KL8.4
Location (hall): 
Fucose
Start/end time: 
Thursday, July 4, 2019 - 11:15 to 11:45
Speaker reference: 
David
Bonnaffé

David Bonnaffé1, Christine Le Narvor1, Aurelien Alix1

1Paris Sud University, Orsay, France

Heparan Sulfate (HS), a member of the Glycosaminoglycan family, is a linear and sulfated polysaccharide displaying a high level of molecular diversity. HS chains interact and modulate the activity of numerous HS binding proteins (HSBP), amongst which validated therapeutic targets [1]. The selective inhibition of a given protein/HS interaction has been attracting increasing interest as an original therapeutic mode of action, especially since the commercialization of Arixtra® [2], the synthetic version of a pentasaccharide sequence specifically recognizing and activating antithrombin-III. To date, it has not been possible to generalize to other HSBP the strategy used to identify this sequence. In Orsay, we aim at overcoming such a bottleneck by conceiving and synthesizing tailored probes to address different aspects of HS biology and devise therapeutic innovation based on the modulation of HS-HSBP interactions [3]. To reach these aims, we developed new methodologies in organic synthesis and optimized each step by determining their critic parameters [4], thus illustrating that glycochemistry represent an ideal playground to revise central concepts in organic chemistry, as well as to initiate original developments and methodologies.

Organic synthesis for tailored probes

References: 
  1. D. Bonnaffé. C. R. Chimie 2011, 14, 29-73. L. Kjellen, U. Lindahl. Curr. Opin. Struct. Biol. 2018, 50, 101-108.
  2. C. A. A. van Boeckel, M. Petitou. Angew. Chem. Int. Ed. Engl. 1993, 32, 1671-1818. M. Petitou, C. A. A. van Boeckel. Angew. Chem. Int. Ed. Engl. 2004, 43, 3118-3133.
  3. A. Lubineau, H. Lortat-Jacob, O. Gavard, S. Sarrazin, D. Bonnaffé, Chem. Eur. J. 2004, 10, 4265-4282. F. Baleux, L. Loureiro-Morais, Y. Hersant, P. Clayette, F. Arenzana-Seisdedos, D. Bonnaffé, H. Lortat-Jacob. Nature Chemical Biology 2009, 5, 743-748. K-K. Arien, F. Baleux, D.Desjardins, F. Porrot, Y-M. Coïc, J. Michiels, K. Bouchemal, D. Bonnaffé, T. Bruel, O. Schwartz, R. Le Grand, G. Vanham, N. Dereuddre-Bosquet, H. Lortat-Jacob, Scientific Reports 2016, 6, article number 34829. C. Debarnot, Y. R. Monneau, V. Roig-Zamboni, V. Delauzun, C. Le Narvor, E. Richard, J. Hénault, A. Goulet, F. Fadel, R. R. Vivès, B. Priem, D. Bonnaffé, H. Lortat-Jacob, Y. Bourne, Proc. Natl. Acad. Sci. USA 2019, 116 (14), 6760-6765.
  4. R. Lucas, D. Hamza, A. Lubineau, D. Bonnaffé, Eur. J. Org. Chem. 2004, 2107-2117. A. Dilhas, R. Lucas, L. Loureiro-Morais, Y. Hersant, D. Bonnaffé. J. Comb. Chem. 2008, 10, 166–169. A. Bernardin, A. Cazet, L. Guyon, P. Delannoy, F. Vinet, D. Bonnaffé, I. Texier, Bioconjugate Chem. 2010, 21, 583-588. G. Povie, A-T. Tran, D. Bonnaffé, J. Habegger, Z. Hu, C. Le Narvor, P. Renaud, Angew. Chem. Int. Ed. 2014, 53, 3894–3898.

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