Axe : Organic Synthesis - Glycomolecules: from synthesis to enzymology
Theme : Glycomimetics
Created in 1997, upon the arrival of Prof. Olivier R. Martin from USA, our team is one of four at ICOA which form the research group "Glycomolecules: from synthesis to enzymology". In addition to Prof. Martin, the team is currently composed of two permanent researchers: Estelle Gallienne, assistant professor since 2008 and Cyril Nicolas, research fellow at CNRS since 2010. The team research activities are to develop original methods of organic synthesis, mainly in the field of carbohydrates, applied to the preparation of new molecules of therapeutic interest.
As well as amino acids, lipids, and nucleotides, "sugars" are a large group of natural products widely found in living organisms. Those substances play a fundamental role from a nutritional, structural and protective point of view. Other more subtle but equally important functions have also been discovered. Thus oligosaccharides of great complexity, grafted on membrane lipids and proteins "decorate" the cell surface. These structures are involved in recognition mechanisms as fundamental as infection by pathogens, antigen-antibody interactions or the triggering of inflammatory signals.
In this context, an important part of our research, on the border between chemistry and biochemistry, is devoted to developing new strategies of organic synthesis to access quickly and, if possible, in an innovative way to small molecules capable of interfering with the biosynthesis or the biodegradation of these carbohydrate structures.
Among the glycomimetics identified to date, iminosugars form a family of particularly interesting molecules. Indeed, the simple substitution of the endocyclic oxygen of sugars by a nitrogen atom opens the way to remarkable biological properties. Historically known as potent inhibitors of glycosidases, the iminosugars are also used for the inhibition of glycosyltransferases, glycogen phosphorylase, UDP-Galp mutase and more recently of metalloproteinases.
As these enzymes are involved in many fundamental biological processes, such compounds therefore have great potential as therapeutic agents.
- Therapeutic agents towards lysosomal storage disorders
The lysosomal storage disorders are rare genetic diseases, which result from the dysfunction of one of the lysosomal enzymes; the organelle responsible for the digestion of the organism macromolecules. Chaperone therapy, on which we focus, is an innovative therapeutic approach. It consists in the administration at low concentrations of small inhibitory molecules that stabilize the three dimensional structure of the deficient enzyme, avoid its degradation, and so allow the hydrolysis of accumulated substrate, significantly reducing the symptoms of the disease. In this context, several iminoglycolipids were designed and synthesized in our group and then evaluated by our collaborators biologists as future therapeutic agents, especially as inhibitors and chaperones of b-glucocerebrosidase, the enzyme responsible for Gaucher disease, or of lysosomal galactosidases, such as b-galactocerebrosidase, involved in Krabbe disease.
- Natural glycolipids analogues: molecules with immunomodulatory activity3
Pro-inflammatory cytokines play a key role in inflammatory, autoimmune or allergic diseases. As current treatments have many side effects, there is a real medical need to find new inhibitors of these cytokines. The Phosphatidyl-Inositol-Mannosides (PIM) are natural glycolipids of low molecular weight with interesting anti-inflammatory activities. Various analogs of PIM were therefore synthesized and found to be strong inhibitors of the in vitro and in vivo inflammatory response in a model of pulmonary inflammation.
- Inhibitors of the biosynthesis of mycobacterial cell wall: towards new anti-tuberculosis agents
Faced with the resistance phenomena increasingly observed, the search for new antibiotics specific of the involved pathogenic microorganisms is necessary. And galactose is a sugar that is present in the furanose form only in microorganisms, such as Mycobacterium tuberculosis, which causes tuberculosis. It has indeed been shown that the galactofuranose and the enzymes the substrate of which it is (GlfTs and Galp mutase) are essential for the development and survival of mycobacteria, which makes these biocatalysts very attractive therapeutic targets. The study of these enzymes should therefore lead to critical information and compounds that inhibit the production or incorporation of these galactofuranose units appear as potential antibacterial agents.
- Innovative synthetic methodologies
We have developed a general strategy for the synthesis of nitrogen-containing polyfunctionalized heterocycles built on the Du Bois amination reaction using carbamates or sulfamic esters. The novelty of our approach is based on an iterative strategy of bonds building, in which key functional groups were designed as "activating molecular arms", thereby allowing the successive functionalization of different positions of the nitrogen-containing heterocycle. Another innovative strategy for the synthesis of iminosugars is currently being developed in the laboratory involving organocatalyzed diastereoselective aldol reactions.