SEMI-SYNTHESIS OF PHOSPHORYLATED GLYCOSAMINOGLYCANS

Glycosaminoglycans (GAGs) are highly complex, anionic, linear polysaccharides extracted from extracellular matrix of animals cells. They are typically composed of disaccharide repeating units, that are very often extensively decorated with sulfate groups. Some of them are exploited in already approved therapeutic treatments, and a significant number of novel drugs are currently under development. Nonetheless, naturally occurring GAGs exhibit variable chemical compositions and biological activities, which could cause unpredictable results during applications (e.g. heparin crisis in 2007). In this frame, in recent years several research efforts have been spent to synthetize artificial GAG mimics. In this context an interesting topic concerns phosphorylated GAGs. Indeed, phosphate vs. sulfate differences in size, polarity, acid-base and chelation properties could lend unreported activities to phosphorylated GAGs, as indicated by an in silico study comparing the structural flexibility and intra- and intermolecular interaction patterns of native GAGs with their phosphorylated counterparts. Actually, this theoretical investigation suggested that phosphorylated GAGs could bind proteins generally with a stronger affinity than their sulfated counterparts and the differences in the binding modes might be highly protein target-dependent. This would propose phosphorylated GAGs as promising, new species to specifically control biochemical processes where the mediating role of sulfated GAGs is crucial. Nonetheless, the preparation of phosphorylated GAGs is still rather underdeveloped. In this communication we present the results of a screening of both multi-step strategies and direct phosphorylation methods – relying upon either standard or innovative phosphorylation reactions – applied on unsulfated GAG-like polysaccharides from microbial sources.