Chemistry of Biomolecules  


  HEADDr MULARD Laurence / lmulard@pasteur.fr
  MEMBERSDr BALEUX Françoise / Dr BAY Sylvie / BOUTET Julien / CHASSAGNE Pierre / COIC Yves-Marie / Dr DESCROIX Karine / EMPTAS Emeline / GANNEAU Christelle / GARNIER Marie-Ange / GROH François / GUERREIRO Catherine / Dr VRASIDAS Ioannis


  Annual Report

The Chemistry of Biomolecules Unit contributes to several multidisciplinary programs aimed at the validation of biological targets of medical interest and at the development of innovative strategies towards glycotherapeutics and/or glycovaccines. Major focus is on the synthesis of new biomolecules derived from carbohydrates, peptides, and conjugates thereof, designed to investigate the role that some proteins, polysaccharides, and glycoconjugates, play in selected diseases or pathogens of concern for human health.

Therapeutic chemistry

By designing and investigating appropriate mutants of the newly identified SDF-1 γ chemokine, we contributed to decipher the mechanisms by which heparan sulfate could differentially orchestrate the SDF-1 mediated directional cell kinesis through specific binding to the chemokine various isoforms. These results open the way to some new understanding of key homeostatic functions and pathological processes mediated by SDF-1/heparan sulfate interaction.

Besides, taking advantage of the key role played by carbohydrates in HIV infection in conjunction with cell receptor (CD4) and coreceptors (CCR5 and CXCR4), we are investigating innovative synthetic glycoconjugates as potent inhibitors of HIV entry into target cells, as demonstrated on both in vitro

Towards new glycoconjugate vaccines

Within the framework of developing a carbohydrate-based vaccine against cancer, we designed the MAG:Tn3, a synthetic immunogen based on the tumor-associated Tn antigen. The MAG:Tn3 associates Tn clusters to a CD4+ T cell epitope on a tetravalent backbone. It is a promising therapeutic vaccine against adenocarcinomas (breast, lung, and prostate cancer, among others). Based on in vivo results obtained in mice and monkey, a phase I/II clinical trial is under consideration for this vaccine candidate. Pre-clinical investigation towards this aim is ongoing.

In the same context, we prepared a synthetic glycopeptide based on the melanoma-associated GM2 ganglioside. This glycopeptide induces human tumor cell-specific antibodies in mice.

As part of a program aimed at developing innovative glycovaccines against endemic bacillary dysentery, we designed the first promising synthetic carbohydrate-based immunogen against Shigella flexneri 2a, the most prevalent Shigella serotype. The key component of the neoglycoprotein of interest is a synthetic pentadecasaccharide shown to act as a functional mimic of the O-antigen moiety of S. flexneri 2a lipopolysaccharide, which was identified as the the major target of protection against homologous infection. In vivo data encourage a pre-clinical investigation for this vaccine candidate.

Besides, taking into account the absolute requirement for broad serotype coverage on the field, we developed efficient multistep syntheses to a panel of fragments of S. flexneri 3a O-antigen. The synthetic oligosaccharides served as probes to identify immunodominant epitopes recognized by protective antibodies.

Keywords: Cancer, Carbohydrates, Chemo-enzymatic synthesis, Chemokines, Glycochemistry, Glycoconjugates, HIV, Mucins, Peptide synthesis, Shigella, Vaccines



  Publications

F. Bélot, C. Guerreiro, F. Baleux, L.A. Mulard (2005).Synthesis of two linear PADRE conjugates bearing a deca- or pentadecasaccharide B epitope as potential synthetic vaccines against Shigella flexneri>serotype 2a infection, Chem Eur J11, 1625-35.

A. Phalipon, C. Costachel, C. Grandjean, A. Thuizat, C. Guerreiro, M. Tanguy, F. Nato, B. Vulliez-Le Normand, F. Bélot, K. Wright, V. Marcel-Peyre, P.J. Sansonetti, L.A. Mulard, Characterization of functional mimics of the Shigella flexneriserotype 2a O-antigen: implications for the development of a chemically defined glycoconjugate vaccine. J Immunol2006, 176, 1686-94. PMID: 19201878

T. Freire, R. Lo-Man, F. Piller, V. Piller, C. Leclerc, S. Bay (2006). Enzymatic large-scale synthesis of MUC6-Tn glycoconjugates for anti-tumor vaccination. Glycobiology,16, 390-401. PMID: 16449349

C. Laguri, R. Sadir, P. Rueda, F. Baleux, P. Gans, F. Arenzana-Seisdedos,
H. Lortat-Jacob (2007). The novel CXCL12gamma isoform encodes an unstructured cationic domain which regulates bioactivity and interaction with both glycosaminoglycans and CXCR4. PLoS ONE2(10): e1110. PMID: 17971873

J. Boutet, L.A. Mulard (2008). Synthesis of 2 tetra- and 4 pentasaccharide fragments of Shigella flexneri serotypes 3a and/or X O-antigens from a common tetrasaccharide intermediate. Eur J Org, 5526-42.



  Web Site

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Activity Reports 2009 - Institut Pasteur
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