Abstract
Global production of pharmaceutical heparin (Hp) is increasing, and the production process from raw mucosal material results in large amounts of waste by-products. These contain lower sulfated Hp-like and heparan sulfate (HS), as well as other glycosaminoglycans, which are bioactive entities with pharmaceutical potential. Here we describe the first purification, structural and functional characterisation of Hp-like and HS polysaccharides from the four major by-product fractions of standard heparin production. Analysis of the by-products by disaccharide composition analysis and NMR demonstrated a range of structural characteristics which differentiate them from Hp (particularly reduced sulfation and sulfated disaccharide content), and that they are each distinct. Functional properties of the purified by-products varied, each displaying distinct anticoagulant profiles in different assays, and all exhibiting significantly lower global and specific inhibition of the coagulation pathway than Hp. The by-products retained the ability to promote cell proliferation via fibroblast growth factor receptor signalling, with only minor differences between them. These collective analyses indicate that they represent an untapped and economical source of structurally-diverse Hp-like and HS polysaccharides with the potential for enhancing future structure-activity studies and uncovering new biomedical applications of these important natural products.
Highlights
The term heparan sulfate (HS) was used originally to describe ‘heparin-like’ compounds that were extracted during the Hp manufacturing process[7,8]
To initially characterise their anionic charge properties, we carried out a comparison by anion exchange chromatography (AEC) on a Hitrap Q HP column
The majority of Fraction A was displaced from the AEC column prior at 1.0–1.2 M NaCl, a small amount of residual material eluted at 2 M NaCl
Summary
The term HS was used originally to describe ‘heparin-like’ compounds that were extracted during the Hp manufacturing process[7,8]. The dual interaction between ATIII and Factor IIa requires a much longer heparin stretch, of at least 15 residues, but the sequence requirements are somewhat more relaxed; higher sulfation levels generally provide increased activity[20,21]. These differences led to the development of low molecular weight heparin (LMWH) with the ability to interact mainly with ATIII and culminated in development of the pentasaccharide drug Arixtra. The findings support the view that Hp by-products provide a rich resource of Hp-like/HS GAGs for structure-activity studies and have the potential to be exploited in future biomedical applications
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