|HEAD||Dr MULARD Laurence / firstname.lastname@example.org|
|MEMBERS||Dr ALVEY Luke / Dr BAHRAMI Fariborz / Dr BALEUX Françoise / Dr BAY Sylvie / BOUTET Julien
COHEN Amandine / COIC Yves-Marie / DELAFOND Nathalie / Dr DESCROIX Karine / DUGUE Laurence
FLEURY Adeline / Dr FREIRE GARD Teresa / Dr GASSE Cécile / GANNEAU Christelle / GARNIER Marie-Ange / GODET Angélique
GROH François / GUERREIRO Catherine / Dr GUILLOU Sandrine / Dr JANIN Yves / Dr JESTIN Jean-Luc / Dr KAMINSKI Alexandre / Dr KIM Tae Hee / LANDIRES Ivan
Dr LUPAN Alexandru / Dr MUNIER-LEHMANN Hélène / MURCIANO Brice / Dr POCHET Sylvie / SARLIN Fabienne / TEJERO Jesus / Dr VICHIER-GUERRE Sophie / Dr VRASIDAS Ioannis
The Organic Chemistry Unit contributes to several multidisciplinary programs dealing with the synthesis of new chemical entities and validation of biological targets of therapeutic interest.
Within the “GPH tuberculosis” program, we have developed two series of original antimycobacterials. The first class of compounds targets nucleotide metabolism by inhibiting nucleoside monophosphate kinases. Interestingly, some inhibitors are also active on Mycobacterium tuberculosis in vitro. The second class stemmed from the structure of a compound with an activity specific to the mycobacteria genus in vitro. The ensuing structure/activity relationship studies led to improved activity.
Within an initiative supported by the «pôle de compétitivité Medicen» and sponsored by the "Région Ile de France”, which includes the private companies Mutabilis and Novexel, we focused on the design of small chemical libraries of new chemical entities. These molecules will be evaluated against models of infectious diseases on screening facilities at the Institut Pasteur as well as in the research centres of our industrial partners.
By designing and investigating appropriate mutants of the newly identified SDF-1γ 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.
Towards new glycoconjugate vaccines
We designed the MAG:Tn3, a synthetic immunogen based on the Tn antigen, as a promising vaccine candidate against breast, lung or prostate cancer. To further extend the scope of our approach to clinical applications, we developed enzymatic syntheses of the tumor-associated mucin MUC6 displaying high densities of the Tn antigen.
Within our anti-infectious subunit vaccine program, we designed a promising synthetic carbohydrate-based immunogen against bacillary dysentery. The key component of this glycovaccine candidate is a synthetic pentadecasaccharide shown to act as a functional mimic of the major protective antigen of the enterobacterium Shigella flexneri 2a.
Identification and/or engineering of new enzymes
Characterization of the newly identified rat RCL, a N-deoxyribosyl-transferase, revealed an original enzyme activity, namely a deoxynucleoside-5’-monophosphate N-glycosidase of potent therapeutic interest. The sequence/structure/activity relationship of this new, recently patented, family of nucleoside catabolic enzymes is under study.
Using phage display, we have developed in vitro protein engineering methods based on selection protocols that allow the analysis of more than 108 proteins. Thermostable DNA polymerases bearing reverse transcriptase activity were selected from Thermus aquaticus DNA polymerase I mutants according to catalytic activity.
Keywords: Antibacterial Agents, Cancer, Carbohydrates, Chemokines, Enzyme evolution, Enzyme in vivo selection, Glycoconjugates, Medicinal chemistry, Nucleosides, Peptide synthesis, Phage display, Nucleoside metabolism enzymes, Shigella, Vaccines
D. Douguet, H. Munier-Lehmann, G. Labesse, S. Pochet (2005). LEA3D: A Computer-Aided Ligand Design for Structure-Based Drug Design. J. Med. Chem. 48, 2457-2468.
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 flexneriserotype 2a infection, Chemistry11, 1625-1635.
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.
S. Vichier-Guerre, S. Ferris, N. Auberger, K. Mahiddine, J. L. Jestin (2006). A population of thermostable reverse transcriptases evolved from Thermus aquaticus DNA polymerase I by phage display. Angew. Chem. Int. Ed. Engl. 45, 6133-6137.
Y. K. Ghiorghi, K. I. Zeller, C. V. Dang, P. A. Kaminski (2007). The c-Myc target gene Rcl (C6orf108) encodes a novel enzyme, deoxynucleoside 5'-monophosphate N-glycosidase. J Biol. Chem. 282, 8150-8156.
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Activity Reports 2007 - Institut Pasteur
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