Esposito, Fabiana (2025) Semi-synthetic polysaccharides for drug-discovery. [Tesi di dottorato]

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Abstract

Polysaccharides are the most abundant biomacromolecules on our planet, possessing enormous structural diversity and functional versatility. They are currently employed for several purposes, both in their natural and structurally modified forms. An important class of natural polysaccharides includes the sulfated ones, ubiquitous in living systems, which play key roles in several biological functions. Among them, sulfated glycosaminoglycans (GAGs), extracted from animals sources, are the most studied ones. They have a lots of biological activities and play pivotal roles in several physio-pathological processes. Thus, various applications as biomaterials and therapeutics have been developed. Despite this, their employment for the formulation of novel drugs may exhibit limitations connected to production costs, batch standardization, immunogenicity, degradability, or other aspects. The biological activities of sulfated polysaccharides often depend on the selective interaction between the sulfate group(s) on polysaccharide backbone and proteins. This suggested that the sulfation pattern might be able to encode specific functional information. The obtainment of semi-synthetic sulfated polysaccharides, by chemical or enzymatic modifications of natural ones, can lead to structures with a controlled and well-defined distribution of sulfate groups within polysaccharide repeating units (also called sulfation pattern), which can facilitate the studies about structure-activity relationships. Besides, semi-synthetic polysaccharides can exhibit new and enhanced biological properties compared to their unmodified counterparts and can also be produced in large quantities at low costs from sustainable sources. In this frame, this project investigated the possibility to obtain regioselective sulfated polysaccharides by chemical modification of natural unsulfated ones. To this aim, three biopolymers were considered: (1) diabolican, a marine-sourced bacterial exopolysaccharide, resembling GAG structure due to the presence, in its backbone, of aminosugars and uronic acids; (2) alginate polysaccharides, produced, for commercial purposes, from brown algae and (3) curdlan, a -1→3-glucan produced, for commercial purposes, from mutant Agrobacterium strains. Species with unprecedented sulfation pattern, some of them showing a well-defined structure, were obtained both by direct regioselective sulfation/desulfation reactions and by multi-step methods, including the use of either cyclic or acyclic protecting groups. Furthermore, the possibility to obtain anionic analogues of sulfated polysaccharides was investigated by functionalization of some hydroxyls with phosphate groups. In silico studies recently appeared in literature suggested that phosphorylated polysaccharides could bind proteins generally with a stronger affinity than sulfated ones, but, to the best of our knowledge, they have been poorly investigated, despite of their interesting perspectives. To fill this gap, a screening of different phosphorylating reagents and/or reaction conditions was performed towards the semi-synthesis of regioselectively phosphorylated bacterial sourced chondroitin and chitosan polysaccharides. Lastly, in collaboration with IBSA Farmaceutici Italia Srl, cross-linked GAGs, characterized by high biocompatibility and optimized for use both in regenerative and aesthetic medicine (e.g. for use in injectable fillers) and in the orthopedic/physiatric field as intrarticular gels for viscosupplementation, have been studied.

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