Osteoarthritis (OA) is a common joint disease characterized by a gradual loss of cartilage and functional modifications of the extracellular matrix components such as glycosaminoglycans (GAGs) and proteoglycans (PGs). Chondrocytes that are present in the joint tissue try to thwart this loss by producing high level of GAGs but the latter are under altered forms. This leads to a local inflammation which causes swelling and pain in the joint. Actual treatments for this disease are only symptomatic, and there is a real need of curative ones with the increasing occurrence of this disease due to the aging of the population.
The strategy of the project is to propose a favorable environment for mesenchymal stem cells to reconstruct the joint matrix by preparing structurally simplified GAG and PG mimetics. The latter could permit to develop a well-defined synthetic extracellular matrix enabling their industrial development in the context of OA. The glycomimetics are based on the sulfation of size-defined malto-oligosaccharides according to a two-step procedure.
The poster is focused on the first procedure which consists in randomly sulfating malto-oligosaccharides in order to evaluate the degree of sulfation required for observing biological effects. Next, the most active GAG mimetics are reducing-end-functionalized by a protected thiol function to further graft them, by thiol-ene click chemistry, to a bacterial polyester backbone modified with pendant alkene groups thus potentially mimicking PGs. The preliminaries biological assays on randomly sulfated maltooligosaccharides (FGF and VEGF binding, cell proliferation) will be shown.
The second part of the project will consist in selectively introduce sulfate groups on maltoheptaose chains thanks to the chemistry of β-cyclodextrins. The aim of this step would be to determine the effect of the sulfation pattern on biological properties.
The authors acknowledge funding support from Agence Nationale de la Recherche (ANR17-CE07-0005 / GAG-LIKE) and Glyco@Alps project (ANR-15-IDEX-02).
- Alexander et al. Exp Biol Med 239 (2014) 1080-1095