Par - 3 février 2009
Major topics, contracts and collaborations
● Antibacterial and antitumoral
Inhibitors of the bacterial translocase MraY
The world-wide emergence of bacterial resistance to various antibiotics requires the discovery novel compounds able to treat the resistant bacterial strains. In that context, our goal is the inhibition of the bacterial translocase MraY, which catalyses the first membrane step of peptidoglycan biosynthesis. The peptidoglycan layer forms part of the bacterial cell wall and protects the cell from osmotic stress macromolecule. It is without any equivalent in eukaryote cells.
In an ongoing program directed to the inhibition of new targets for fighting antibiotic resistance, we develop two complementary approaches for the design and the synthesis of new inhibitors of MraY :
-Synthesis of liposidomycins analogs
Liposidomycins are in vitro known natural inhibitors of the translocase MraY (ID50 = 0,03 g/mL for liposidomycin C), but none of them display high antibacterial activity, probably due to their high hydrophilicity which limits their passive diffusion through biological membranes. Our goal is to develop access to new MraY inhibitors displaying both simplified structures as compared to the natural ones and enhanced biological activities. The structures of the targeted inhibitors retain either the central diazepanone core of liposidomycins or an aminoribosyl-O-uridine like skeleton.
Liposidomycins and some synthesized analogs
Synthesis of UDP-N-Ac-glucosamine analogs
UDP-Mur-N-Ac-pentapeptide is the natural substrate of MraY which catalyses the Lipid I formation. Then, MurG synthesizes on the cytosolic side of the plasma membrane a polyprenyl-linked precursors, Lipids II, that carries one complete cell wall subunit. Our goal is the synthesis of stable bioisosteres of MraY substrate by replacement of the diphosphate moiety. We first targeted the synthesis of -ketophosphonate bioisostere of UDP-Glc-N-Ac as a possible precursor of UDP-Mur-N-Ac-pentapeptide
Enzymes substrate and its 1C-linked -ketophosphonate bioisostere synthesized
The biological activity of the synthesized inhibitors is evaluated on the purified translocase MraY in collaboration.
Collaborations : D. Mengin-Lecreulx, D. Blanot, laboratoire des enveloppes bactériennes et antibiotiques (CNRS UMR 8619 Paris XI) et S. Gobec, Université de Ljubljana (Slovénie).
Contrat : européen du 6ème PCRDT, Projet Intégré Life Sciences, genomics and biotechnology for health intitulé « EUR-INTAFAR » Inhibition of New TArgets for Fighting Antibiotics Resistance (2005-2009).
● Methionine Aminopeptidases inhibitors : bengamide analogues
An essential step for the maturation of proteins is the hydrolitical removal of N-terminal methionine from newly synthesized polypeptide chains, which is catalyzed by Methionine Aminopeptidases (MetAP1 and MetAP2). These metalloprotases, have been shown to be involved in cell growth and tumor progression, making them potential intracellular targets for the discovery of new anti-cancer drugs.
Among the different inhibitors known to date, Bengamides, secondary metabolites which have been extracted from marine sponges, are potent inhibitors for both isoforms of human MetAP. These natural compounds have been demonstrated to act as reversible substrate-like inhibitors.
Based on known X-ray crystal structures of human MetAP2 complexes with various inhibitors, we are currently developing straightforward syntheses of new Bengamides analogues displaying several structural modifications, thus aiming at the identification of new inhibitors possessing easily accessible structures and potent in vitro and in cellulo activities.
Collaborations : Drs Isabelle Artaud, Armelle Melet and Pr Christiane Garbay (UMR 8601), and Dr Thierry Meinnel (Institut des Sciences du Végétal, UPR2355 CNRS at Gif sur Yvette).
● Inhibitors of tyrosine kinase (FGFR3)
FGFR3 is one of the four receptors for the Fibroblast Growth Factor family whose tyrosine kinase (TK) activity is involved in proliferation and/or cellular differentiation. Specific mutations, germinal or somatic, identified in the various domains of the receptor are producing a constitutive activation of the kinase activity, resulting in over-phosphorylation associated with malignant carcinomas (bladder, cervical cancers), multiple myeloma, genetic disorders of bone growth (chondrodysplasias).
Our goal is to design a new class of TK inhibitors able to mimic ATP and to specifically block the constitutive activation of FGFR3 in vitro and in vivo. The biological activity of these new inhibitors, their effect on the receptor autophosphorylation and on the phosphorylation of the targeted proteins, is evaluated in collaboration. In that context, we became interested in the :
synthesis of C-nucleosidic ATP mimics from enantiomerically pure C2-symmetrical bis-époxydes issued from D-mannitol :
-synthesis of analogs of no specific known inhibitors, with an indolinone or pyridopyrimidine skeleton by click-chemistry :
Collaborations : F. Radvanyi, Laboratoire de Morphogénèse Cellulaire et Progression Tumorale, CNRS UMR 144 et L. Legeai-Mallet, Unité de génétique et épigénétique des maladies métaboliques neurosensorielles et du développement, Inserm U781.
Contrats : ACI (2001-2004), GIS-Institut des maladies rares (2005-2007) et BQR Université Paris 5 (2007).
● Prodrugs of mannose-1-phosphate for potential CDG-Ia therapy
The Congenital Disorders of Glycosylation (CDG) belong to a group of inherited multisystem metabolic disorders characterised by the abnormal glycosylation of a number of serum glycoproteins. The most common clinical case associates an encephalomyopathy and a peripheral neuropathy. Among the identified CDG, CDG-Ia is the most frequently encountered (500 cases in the world among which 100 in France). It is related to an enzymatic deficiency in phosphomannose mutase 2 which catalyses the isomerisation of mannose-6-phosphate into mannose-1-phosphate.
To overcome the defiency in mannose-1-phosphate (M1P), the goal is on one hand the synthesis of prodrugs able to generate mannose-1-phosphate in the cytosol, and one the other hand the biological evaluation of these prodrugs. The targeted prodrugs of M1P are mono, di and tri-mannopyranosyl phosphates for which the hydroxyl groups of the sugar moiety are protected in order to modulate the lipophilicity. A special attention is paid to the introduction of R1 and/or R2 groups with no or weak toxicity :
Targeted prodrugs of mannose-1-phosphate
Collaborations : P. de Lonlay, Hôpital Necker-Enfants Malades, Service des Maladies Métaboliques, et S. Moore, T. Dupré, Centre de Recherche Biomédicale Bichat Beaujon INSERM U773, Faculté de Médecine Xavier Bichat).
Contrat : Orphan-Europe/CNRS/Université Paris 5 (2004-2006).
Design and synthesis of new α-amino acid mimetics based on pipecolate and cyclic lysine scaffolds with adjustable i dihedral angles, aiming at various applications such as :
Mimetics of proline and 4-hydroxyproline for the development of prolyl peptide isomerases (PPIases) inhibitors,
Mimetics of the RGD triade, a major recognition system for cell adhesion,
Inhibitors of NO synthases (NOS).
Collaboration : Dr Jean-Luc Boucher (UMR 8601).
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