UPR 5301

Rubal RAVINDER’ s thesis defense on December 7th, 2020

This thesis is entitled "Synthesis of (cyclo)maltooligosaccharides-based sulfated glycosaminoglycan mimetics and their interaction with heparin binding growth factors" and is co-supervised by M. Sami HALILA, CNRS researcher at Cermav- UPR5301, and M. Romain VIVES, Research Director at Institut de Biologie Structurale - UMR5075.

“Osteoarthritis (OA) is the most common joint disease, characterized by gradual loss of articular cartilage due to abnormal extracellular matrix (ECM) and changes in chondrocyte morphology and metabolism, associated to sub-endochondral bone remodeling and local synovitis. The burden of this disease has been gradually gaining importance in the last few decades with the aging of the population and the obesity epidemic. Beyond the huge healthcare costs for treatment of OA affecting 70 million individuals in Europe, there is no treatment that can repair the cartilage and stop the progress of OA. Existing therapies, based on hyaluronic acid and chondroitin sulfate injections, are symptomatic and pursue only pain alleviation with no effect on slowing disease progression and on restoring cartilage and chondrocytes functions. In parallel, new therapeutic strategies are currently based on stem cells, but these fragile cells are injected in an inflammatory microenvironment detrimental to their survival and clinical efficacy. Therefore, a more suitable middle is highly mandatory. Our project is born from the observation that OA is closely related to a loss of proteoglycans (PGs), one of the largest component of the ECM. These PGs are not only structural components, but regulators of cell functions also since they interact with growth factors, cytokines, proteinases, adhesion receptors and extracellular matrix components through their sulfated glycosaminoglycan (GAGs) chains. As a consequence, these polysaccharides are new important classes of molecular targets in the fields of biochemistry, pathology and pharmacology. However, due to the natural extractive source of PGs and GAGs and their inherent complexity in terms of relative molecular mass, charge density, sulfation patterns, the relationship with functions are difficult to elucidate and their therapeutic and commercial use is complicated according to their poorly defined structures. Use of well-defined biomimetic structures are therefore the valuable alternatives for therapeutic strategies. Attemps have relied on the idea that a limited number of anionic groups (e.g., sulfate, carboxylate, phosphate) on a smaller oligosaccharide scaffold may overcome the difficulties of working with GAGs or PGs. Examples of these include GAG related polysaccharides of non-mammal origin that have shown to stimulate healing of tissues with similar or higher efficiency than natural GAGs or PGs. And, very recently, glycopolymers based on oligosaccharide repeating units constituting GAG structures have been reported and revealed fascinating ability to recapitulate biological features of natural PGs. Even if only GAGs oligomers (di- up to penta-saccharides) were targeted, their syntheses still pose significant challenges. These shortcomings can be remedied by designing readily accessible GAG oligosaccharide mimetics in order to tune their 3-D structure and to fit the biological binding sites. Additionally, as for natural PGs, multi-presentation of GAG mimetics is an essential task to evaluate the significance of this parameter. Up to date, these approaches have never been investigated, especially in order to promote the articular cartilage homeostasis. Our project aims to develop PG-like biopolymers made of architecturally defined grafted polyesters having simplified sulfated GAG mimetics. These glycomimetics will be assessed for their abilities to interact with growth factors binding to natural GAGs by stimulating cell growth. Forces aligned within this consortium combined crucial expertise in chemo-enzymatic modification of oligosaccharides (CERMAV, Grenoble), in the preparation of functional polyesters (ICMPE, Paris Est), and in the study of GAGs on the mesenchymal stem cells properties (Gly-CRRET, Paris Est & IBS-Grenoble).”