|Chemistry of Biomolecules - CNRS URA 2128|
|HEAD||Dr MULARD Laurence / email@example.com|
|MEMBERS||ARGILES Geoffrey / Dr BALEUX Françoise / Dr BAY Sylvie / CHASSAGNE Pierre / COIC Yves-Marie / COURTIOL Tiphanie / EMPTAS Emeline / GANNEAU Christelle / GARNIER Marie-Ange / Dr GAUTHIER Charles / GROH François / GUERREIRO Catherine
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 chemical entities and 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.
A synthetic glycopeptide issued from the covalent linking of a CD4 peptide mimetic to an heparan sulfate (HS) dodecasaccharide, was proposed as a new HIV entry inhibitor. The CD4 mimetic binds to gp120, induces the conformational change that exposes the CD4 induced epitope, which in turn is locked by the HS fragment. The covalent linkage between the CD4 mimetic and the HS oligosaccharide provides strong cooperative effects, resulting in a low-nanomolar antiviral activity towards both CCR5- and CXCR4-tropic HIV-1 strains when evaluated on PBMC.
In the search for NEMO oligomerization inhibitors, we synthesized doubly labelled NEMO peptides (84 AAs) for FRET experiments. Besides, the synthesis of a 54 AAs caveolin-1 peptide encompassing the intramembrane domain to enrich structural investigations on membrane proteins, is another example of our contribution in the challenging synthesis of long peptides.
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 need for broad serotype coverage on the field, we developed efficient multistep chemical syntheses of fragments of S. flexneri 3a O-antigen.
As a contribution to innovation in the synthesis of complex microbial cell-surface oligosaccharides, we also reported in vitro chemo-enzymatic pathways that take advantage of enzyme engineering. Transglycosidases were designed on purpose to produce intermediates compatible with a programmed chemical elongation from nonnatural conveniently protected substrates.
Keywords: Cancer, Carbohydrates, Chemo-enzymatic synthesis, Chemokines, Glycochemistry, Glycoconjugates, Glycoenzymes, HIV, Mucins, Peptide synthesis, Shigella, Vaccines
Baleux, F. ; Loureiro-Morais, L. ; Hersant, Y. ; Clayette, P. ; Arenzana-Seisdedos, F. ; Bonnaffé, D. & Lortat-Jacob, H. (2009).A synthetic CD4-heparan sulfate glycoconjugate inhibits CCR5 and CXCR4 HIV-1 attachment and entry. Nat Chem Biol,5, 743-8. PMID: 19734912.
Bay, S.; Fort, S.; Birikaki, L.; Ganneau, C.; Samain, E.; Coïc, Y-M.; Bonhomme, F.; Dériaud, E.; Leclerc, C.; Lo-Man, R.(2009). Induction of a Melanoma-Specific Antibody Response by a Monovalent, but not a Divalent, Synthetic GM2 Neoglycopeptide. ChemMedChem, 4, 582-7. PMID 19226501.
Boutet, J.; Guerreiro, C.; Mulard,L. A. (2009). Efficient synthesis of six tri- to hexasaccharide fragments of Shigella flexneriserotypes 3a and/or X O-antigen including a study on N-trichloroacetylglucosamine- versus N-acetylglucosamine-containing acceptors. J Org Chem, 74, 2651-70. PMID: 19278208.
Champion, E. ; André, I. ; Moulis, C. ; Boutet, J. ; Descroix, K. ; Morel, S. ; Monsan, P. ; Mulard,L. A. ; Remaud-Siméon M. (2009). Design of new transglucosidase activities for innovative chemo-enzymatic synthesis of complex microbial oligosaccharides. J Am Chem Soc, 131, 7379-89.PMID: 19432472. PMID: 19226501.
Phalipon, A.; Tanguy, M.; Grandjean, C.; Guerreiro, C.; Bélot, F.; Cohen D.; Sansonetti, P.J.; Mulard, L. A.(2009). A synthetic carbohydrate-protein conjugate vaccine candidate against Shigella flexneri2a infection. J Immunol, 82, 2241-7.PMID: 19201878.
Activity Reports 2009 - Institut Pasteur
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